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Author: kodiac

Domagrozumab

Plain-language summaryIntrigue 50 / 100

Domagrozumab (PF-06252616) is Pfizer’s second-generation anti-myostatin antibody, designed for higher affinity than stamulumab. The pivotal phase 2 trial in Duchenne muscular dystrophy (2018) showed meaningful muscle mass increases on MRI but failed to demonstrate functional benefit on the primary motor outcome, leading Pfizer to terminate the program. The pattern (muscle mass without function) has now repeated across nearly every anti-myostatin compound tested in muscular dystrophy and is the central puzzle of the field: blocking myostatin reliably grows muscle but does not seem to make patients meaningfully stronger. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundNiche research probe

32/100

Failed DMD phase 2 retained as a selective myostatin probe for mechanistic research

Look, the anti-myostatin story has not gone well for anyone. Wyeth’s stamulumab, Lilly’s landogrozumab, Regeneron’s trevogrumab – the list of humanized antibodies that neutralized myostatin beautifully in animals and then failed in humans is long enough now that we have to take the lesson seriously. Domagrozumab is the Pfizer entry in that cohort, and its 2018 phase 2 in DMD produced the most clinically instructive kind of failure: muscle mass went up on MRI, but the 6-minute walk test and North Star Ambulatory Assessment didn’t move.

That result isnt just a dead end – its actually the most scientifically interesting thing about this compound. It suggests the limiting factor in DMD isnt myostatin-mediated mass suppression; its the relentless mechanical damage from dystrophin deficiency. You can add muscle, and the dystrophic fiber still breaks down faster than myostatin inhibition can compensate. Thats genuinely clarifying biology, and domagrozumab helped establish it.

The novelty problem is real. Myostatin inhibition as a concept is nearly thirty years old – the McPherron double-muscle mouse dates to 1997. The IgG1 antibody approach to neutralizing GDF-8 is well-trodden at this point, and domagrozumab doesnt have a mechanism angle that distinguishes it meaningfully from the compounds that came before. Its not doing anything the class hadn’t already tried, and the mechanism score reflects that: single-receptor neutralization in a saturated, largely-failed class.

Differentiation is the weakest score here. Against other anti-myostatin antibodies, domagrozumab occupies no particular best-in-class position. Its affinity for myostatin is high, it’s humanized, its PK in humans is characterized – that makes it a functional research tool, but not a leading one. We think the ActRII-pathway inhibitors (luspatercept, bimagrumab) are more interesting if you want to study muscle anabolism broadly, because they engage the wider TGF-beta ligandome and produce cleaner clinical signals.

What domagrozumab does retain is probe value for investigators who specifically want myostatin-selective inhibition, as opposed to the broader ligand traps that catch activin, GDF-11, and other TGF-beta family members alongside GDF-8. If your question is specifically about GDF-8 rather than the whole ActRIIB ligandome, this compound gives you a cleaner experimental handle. Thats a narrow utility but its real.

The phase 2 evidence is actually quality evidence – well-designed RCT, adequate N, prespecified functional endpoints – it just produced a negative answer. The evidence quality score is respectable for that reason. The translational signal, though, is genuinely negative: the mechanism did not translate to clinical benefit in the target population, and that distinction matters for how we weight this overall.

Bench scientists studying DMD pathophysiology, the myostatin signaling axis, or the dissociation between muscle mass and functional output in dystrophic tissue will find this a documented, human-characterized probe. For everyone else, the evidence has made the case for moving on.

Novelty

28

Mechanism promise

35

In-category differentiation

20

Evidence quality

50

Translational signal

22

Research bench value

48

Rationale Domagrozumab’s 2018 phase 2 in DMD decisively closed the clinical case: muscle mass increases on MRI did not translate to functional gains, and Pfizer walked away. Scores are suppressed by low novelty in a 25-year-old target class, no meaningful differentiation from other failed anti-myostatin antibodies, and a clearly negative translational signal; residual probe value for GDF-8-selective biology keeps bench_value from bottoming out.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Anti-myostatin monoclonal antibody

A humanized anti-myostatin monoclonal antibody developed at Pfizer for Duchenne muscular dystrophy; phase 2 trial failed.

Abstract

Domagrozumab (PF-06252616; humanized IgG1 monoclonal antibody; molecular weight approximately 145 kDa) is a humanized anti-myostatin monoclonal antibody developed at Pfizer. The compound is selective for myostatin (GDF-8) with high affinity, designed to neutralize circulating myostatin in Duchenne muscular dystrophy. Phase 2 trial in DMD (2018) demonstrated muscle mass increases on MRI but no significant improvement in functional endpoints (6-minute walk test, North Star Ambulatory Assessment); Pfizer discontinued development. The trial result reinforced a broader concern about myostatin inhibition in DMD: muscle mass gains may not translate to clinical benefit if the underlying dystrophin deficiency continues to cause fiber damage. Used as a research compound for selective myostatin neutralization in DMD context.

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The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

May 9, 2026
Bimagrumab

Plain-language summaryIntrigue 64 / 100

Bimagrumab is a humanized antibody against the activin receptor type II (the receptor that myostatin and related ligands bind) developed by Novartis and MorphoSys. By blocking the receptor at the cell surface, it prevents engagement by myostatin, activin A, and GDF-11 in one shot. It has been investigated for sporadic inclusion body myositis, sarcopenia, and (more recently) obesity-related muscle preservation, where it has produced meaningful fat loss alongside muscle gain in early trials. Most trials have not met primary endpoints in muscle disease populations, but the obesity application has revived clinical interest. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundNovel, promising

65/100

Receptor-level ActRII blocker with an unusual fat-loss plus muscle-gain profile that stands apart in the GLP-1 era

Look, the myostatin inhibitor space has a graveyard in it. ACE-031 was stopped for safety. Stamulumab showed muscle signal in Becker but couldnt replicate it cleanly. The whole class got written off by a lot of investigators around 2015. Bimagrumab is the compound that survived that shakeout, and the reason it survived is that it’s doing something structurally different from its predecessors.

Most myostatin pathway inhibitors are ligand traps or single-ligand antibodies. Bimagrumab binds ActRIIA and ActRIIB directly at the receptor level, which means it blocks myostatin, activin A, and GDF-11 in one shot. That’s not a marginal technical distinction. Activin A in particular is now understood to be a co-driver of muscle wasting in several contexts, and blocking it alongside myostatin gives a broader suppression of the pathway than a selective antibody can achieve. That’s the mechanism we find genuinely interesting here.

The RESILIENT trial in sporadic inclusion body myositis showed lean mass gains. The sarcopenia work showed lean mass gains. Those are real, replicated signals in two different wasting contexts. But the thing that really sharpened our interest is the 2020 BIM-T2D phase 2 data, where bimagrumab produced roughly 21 percent fat mass reduction alongside muscle preservation in obese patients with type 2 diabetes. That combination profile is unusual. Most pharmacological interventions that drive fat loss also drive some lean mass loss. Bimagrumab’s direction of effect is inverted on the muscle side, and that matters enormously now that GLP-1 agonists are being criticized for the lean mass loss they produce during rapid weight reduction.

Honestly, the timing here matters as much as the mechanism. If this data had come out in 2014 it would have been interesting but not urgent. Coming out in 2020 and being developed further in parallel with semaglutide and tirzepatide’s rise, the muscle-preserving fat loss profile is suddenly one of the more clinically relevant compound profiles in the space. Novartis has continued development, and there are combination-with-GLP-1 trials being discussed or initiated.

What we dont like: the evidence base is still mostly phase 2. The fat mass reduction finding needs phase 3 confirmation. And the underlying ActRII biology, while elegant, is not fully de-risked. Off-target effects on reproductive biology and bone are a real pharmacology concern at this receptor level. As a research probe for receptor-level myostatin pathway biology, it’s genuinely the cleanest tool available. As a compound, its overall profile is strong enough to warrant serious attention but not yet the finished story.

Novelty

62

Mechanism promise

73

In-category differentiation

65

Evidence quality

60

Translational signal

65

Research bench value

60

Rationale Bimagrumab scores well on mechanism and differentiation because its ActRII receptor-level blockade is mechanistically distinct from failed ligand traps and selective myostatin antibodies, and the 2020 BIM-T2D phase 2 data showing ~21% fat mass reduction with concurrent lean mass gain is genuinely unusual. Novelty is held down somewhat because the compound has been in clinical development since roughly 2013; the obesity angle is fresh but the underlying biology is a decade old.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Anti-activin receptor type II monoclonal antibody

A humanized monoclonal antibody against activin receptor type II; investigated for sarcopenia, sIBM, and obesity-related muscle preservation.

Abstract

Bimagrumab (BYM338; humanized IgG1 monoclonal antibody; molecular weight approximately 145 kDa) is a humanized monoclonal antibody against activin receptor type II (ActRII), developed at MorphoSys and Novartis. The compound binds ActRIIA and ActRIIB receptors on the cell surface, blocking access by myostatin, activin A, and GDF-11; the receptor-level blockade is mechanistically distinct from ligand traps (ACE-031) and from selective myostatin antibodies (stamulumab). Phase 2 trials in sporadic inclusion body myositis (RESILIENT) and sarcopenia demonstrated muscle mass increases. The compound generated substantial interest in 2020 after a phase 2 trial in obesity with type 2 diabetes (BIM-T2D) showed approximately 21 percent reduction in fat mass with concurrent muscle preservation, an unusual profile that has subsequently driven obesity-related development. Used as a research probe for receptor-level myostatin pathway inhibition.

Read the full monograph

The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

May 9, 2026
Buprenorphine

Plain-language summaryIntrigue 76 / 100

Buprenorphine is a semi-synthetic opioid with an unusual receptor profile that has made it the cornerstone of medication-assisted treatment for opioid use disorder. As a high-affinity partial mu-opioid agonist it activates the receptor enough to suppress withdrawal and craving but with a built-in ceiling on respiratory depression that makes overdose much less likely than with full agonists. Its kappa antagonism may contribute to mood benefit. The combination with naloxone (Suboxone) discourages injection abuse because naloxone is not orally active but blocks opioid effects if injected. Approved for OUD in the US in 2002, it has saved many lives. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundFederally scheduled

57/100

Mature Schedule III MAT agent with a genuinely interesting KOR antagonism angle but limited frontier research appeal

Look, buprenorphine is one of the most clinically important opioid-system compounds ever developed, and that’s precisely why it scores where it does here. The evidence base for OUD treatment is enormous: multiple FDA approvals, decades of real-world data, a well-characterized safety margin built on mu partial agonism. But clinically essential and interesting research target right now are two different questions, and this rubric is asking the second one.

The pharmacology is genuinely interesting. What buprenorphine does is unusual: high-affinity mu binding (Ki approximately 0.2 nM) with roughly 30 percent intrinsic activity, which produces analgesia and craving suppression without the respiratory depression ceiling you get from full agonists. And then layered on top, concurrent kappa-opioid antagonism and ORL1 partial agonism. That’s a legitimately complex pharmacological profile. The KOR antagonism is the angle that keeps serious investigators paying attention. KOR activation is strongly implicated in dysphoria and stress-driven depression, so blocking it while partially activating mu has real mechanistic rationale as an antidepressant approach. Some early clinical data support this, though effect sizes are modest and the literature is still maturing.

Here’s the problem with using buprenorphine as the probe for that question: the mu signal is always in the room. Selective KOR antagonists like aticapant or navacaprant give you cleaner experimental handles on the kappa axis in isolation. With buprenorphine, any behavioral or molecular readout you get in a model is a convolution of at least three receptor activities. Thats not fatal for all research designs, but it limits interpretability in a way that matters for mechanistic work.

From a bench value standpoint, it remains a useful reference tool. If your program involves opioid receptor partial agonism dynamics, tolerance and ceiling-effect modeling, or mu/kappa crosstalk, buprenorphine is the canonical standard. We credit that. The Schedule III status creates meaningful practical friction for investigators who aren’t already operating in a controlled-substance-licensed environment, which is worth acknowledging honestly.

What we don’t see is a strong case for building a new research program around buprenorphine in 2025 unless that program is specifically about OUD pharmacotherapy refinement, KOR biology in mood disorders where selectivity constraints are acceptable, or receptor pharmacology where a mu partial agonist reference is genuinely needed. Important compound, belongs in the library, but isnt where the frontier is.

Novelty

22

Mechanism promise

60

In-category differentiation

58

Evidence quality

78

Translational signal

72

Research bench value

65

Rationale Buprenorphine’s clinical evidence base for OUD is massive but that’s not what drives research scores; novelty is low given a 1981 approval and decades of trodden literature. The kappa-opioid antagonism angle for treatment-resistant depression is the one live research thread, but it’s mechanistically muddied by concurrent mu partial agonism, and cleaner selective KOR antagonists exist as investigational probes. Schedule III cap of 75 does not bind since the calculated score falls below it.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Mu-opioid partial agonist + kappa-opioid antagonist

A semi-synthetic mu-opioid partial agonist with kappa-opioid antagonism; the primary medication-assisted treatment for opioid use disorder.

Abstract

Buprenorphine ((2S,6R,7R,14S)-17-cyclopropylmethyl-7-[(S)-1-hydroxy-1,2,2-trimethylpropyl]-6-methoxy-4,5-epoxy-6,14-ethano-morphinan-3-ol; CAS 52485-79-7; molecular formula C29H41NO4; molecular weight 467.65) is a semi-synthetic thebaine-derived mu-opioid partial agonist with concurrent kappa-opioid antagonist and ORL1 (nociceptin receptor) partial agonist activity. Originally approved by the FDA in 1981 as an analgesic; reformulated and approved in 2002 (Subutex, Suboxone) for opioid use disorder. Mu-opioid affinity is high (Ki approximately 0.2 nM) with intrinsic activity approximately 30 percent (partial agonism); the partial agonism produces a ceiling effect on respiratory depression and euphoria, distinguishing buprenorphine safety profile from full agonists like fentanyl or morphine. Long plasma half-life (24 to 60 hours) supports once-daily or less-frequent dosing. Suboxone formulation includes naloxone (a mu antagonist with poor sublingual bioavailability) to deter intravenous misuse. Approved for opioid use disorder and chronic pain (transdermal Butrans). The kappa-opioid antagonism is being investigated for treatment-resistant depression. Used as the canonical mu-opioid partial agonist in addiction medicine.

Read the full monograph

The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

May 9, 2026
Naloxone

Plain-language summaryIntrigue 64 / 100

Naloxone, sold as Narcan, is the standard reversal agent for opioid overdose. It competitively binds and displaces opioids from the mu-opioid receptor with high affinity, restoring breathing within minutes when administered intramuscularly or as an intranasal spray. Public health programs have made intranasal naloxone available without prescription in pharmacies and from harm-reduction organizations across most of the US, and bystander administration is credited with thousands of overdose reversals annually. The short half-life means re-dosing may be required for long-acting opioids like methadone or fentanyl analogs. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundNiche research probe

50/100

The canonical opioid antagonist probe; indispensable in its niche but far from a novel research target

Look, naloxone isnt a research target. It’s a research tool. That distinction matters a lot when you’re trying to explain a score of 50, which might seem high for a compound that scores 12 on novelty and 22 on mechanism promise. The thing is, those two axes tell the truth about where naloxone sits right now: it’s a 1971 FDA approval with a completely understood competitive antagonism profile at mu-opioid receptors (Ki approximately 1 nM), and nobody in the field is surprised by any of that. The pharmacology is textbook. The mechanism is single-receptor competitive antagonism, about as mechanistically unexciting as it gets for a research library context.

So why does it score 50 at all? Because evidence quality and translational signal are very real, and bench value is genuinely high. As the canonical short-acting, reversible mu-opioid antagonist, naloxone is what you reach for when you want to attribute an effect to opioid receptor activation. You can’t do serious opioid pharmacology without it. In animal behavioral models, in ex vivo receptor binding, in cell culture signaling studies, naloxone is the probe that closes the loop. There’s a reason every paper on endogenous opioids, opioid-mediated analgesia, or itch involves a naloxone blockade condition. It’s not doing anything exciting on its own; it’s the negative control that makes everything else interpretable.

The evidence base is essentially unimpeachable. FDA approved since 1971. Decades of replicated clinical data on reversal efficacy. The intranasal 4 mg formulation has generated real public health outcome data, and the overdose reversal pharmacokinetics are thoroughly characterized across parenteral and mucosal routes. You’re not going to find an evidence-quality problem here. Translational signal similarly scores high because the clinical effect is binary and unambiguous. That’s about as clean a human signal as this field produces.

What we don’t love is the novelty situation. There’s essentially no fresh angle here for a general-purpose research program. Some investigators are poking at ultra-low-dose naloxone in paradoxical opioid sensitization models, and the toll-like receptor 4 story (the non-stereoselective TLR4 binding that the (+)-naloxone isomer isolates) is genuinely interesting mechanistic territory, but that angle hasnt produced clinical traction and remains a niche debate. The low-dose naltrexone literature is adjacent but uses a different compound with a different half-life and a different evidence trajectory.

We think naloxone belongs in the library as a reference compound: the thing you want well-documented and accessible for any research program that touches opioid receptor modulation. Its score reflects exactly what it is, high value in a specific and narrow research context, low value as a forward-looking research target. The 50 is earned by half the formula, and the other half is where it tells on itself.

Novelty

12

Mechanism promise

22

In-category differentiation

52

Evidence quality

88

Translational signal

85

Research bench value

72

Rationale Naloxone earns its 50 from very high evidence quality and translational signal as a 55-year FDA-approved clinical compound, offset by essentially zero novelty and unremarkable single-receptor mechanism; its library value is as the reference mu-antagonist probe for opioid receptor pharmacology, not as a forward-looking research target.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Mu-opioid antagonist (short-acting)

A short-acting mu-opioid antagonist; the standard reversal agent for opioid overdose.

Abstract

Naloxone ((5alpha)-4,5-epoxy-3,14-dihydroxy-17-(2-propenyl)morphinan-6-one; CAS 465-65-6; molecular formula C19H21NO4; molecular weight 327.37) is a short-acting mu-opioid antagonist approved by the FDA in 1971 (Narcan). The compound is a competitive antagonist at mu, kappa, and delta opioid receptors with preferential mu affinity (Ki approximately 1 nM). Unlike naltrexone, oral bioavailability is poor (less than 5 percent), restricting use to parenteral or intranasal administration. Plasma half-life is approximately 1 to 2 hours, shorter than most opioid agonists, requiring multiple doses or infusion in opioid overdose reversal where the half-life of the offending opioid exceeds naloxone’s. The intranasal formulation (Narcan nasal spray, 4 mg) is widely available and has driven the modern public health response to the opioid overdose epidemic. Approved indications: opioid overdose reversal, postoperative opioid reversal, opioid-induced constipation (IV form alvimopan, methylnaltrexone for that latter). Used as the canonical mu-opioid antagonist in research.

Read the full monograph

The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

KDC-MN-352Open in new tab →

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

May 9, 2026
Low-Dose Naltrexone (LDN)

Our opinion on this compoundNiche research probe

48/100

Genuinely interesting neuroimmune probe with patchy clinical evidence and an old backbone

Look, the compound itself is ancient. Naltrexone got FDA approval in 1984, and the low-dose angle dates to Bernard Bihari’s clinical observations in the late 1980s. So when we talk about LDN as a research target, we’re not talking about freshness. What we are talking about is a genuinely unusual pharmacological story that most people in the opioid receptor space still dont fully understand.

Here’s the thing that makes LDN interesting: the mechanism isn’t just “antagonize the mu receptor at low dose and call it a day.” The working model involves a brief 4-6 hour blockade that triggers compensatory receptor upregulation and increases in endogenous opioid synthesis — net effect is actually elevated opioid tone over baseline, the opposite of what you’d expect. Layer on top of that the TLR4 antagonism story, where naltrexone’s action on microglial Toll-like receptor 4 attenuates neuroinflammatory signaling through a completely separate pathway. That’s a two-pronged mechanism with real conceptual bite, and the neuroimmune piece is what drives most of the current bench interest.

The problem is the evidence base. We have clinical trials across fibromyalgia, multiple sclerosis, Crohn disease, Hashimoto thyroiditis, and CRPS — but almost all of them are small-N, single-center, and methodologically inconsistent. The Penn fibromyalgia work from Younger’s group is probably the most methodologically serious, and even that produced modest effect sizes. There’s no phase 2/3 replication that would let you say “this is settled.” The translational signal is real in the sense that human subjects clearly respond to something, but “why” remains incompletely characterized and the effect magnitude across populations is not compelling.

What we think is genuinely valuable here is the bench probe application: LDN is a useful tool if you’re studying microglial TLR4 signaling, paradoxical receptor pharmacology, or neuroimmune crosstalk. You can ask questions with it that you can’t ask as cleanly with other compounds in this space. The compounding availability is solid and the base compound’s pharmacokinetics are extremely well-characterized, which means experimental design is tractable. For investigators working at the neuroimmune interface, having LDN in the toolkit makes sense.

What we don’t like: the clinical literature is genuinely messy. Patient advocacy communities have generated most of the pressure to study LDN, which introduces selection bias and publication pressure that makes the human signal harder to parse. If you’re trying to build a rigorous case for any single indication, you’re working against decades of underpowered trials. Interesting compound, credible mechanism, limited evidence base. That combination lands it squarely in the useful-but-not-compelling range for most research programs outside of the neuroimmune niche it was built for.

Novelty

35

Mechanism promise

58

In-category differentiation

52

Evidence quality

42

Translational signal

47

Research bench value

58

Rationale LDN’s dual mechanism — paradoxical opioid tone upregulation plus TLR4/microglial antagonism — is more interesting than a plain receptor story, but naltrexone is a 1984 FDA approval and the LDN angle has been circulating since Bihari’s work; novelty is limited. Evidence across MS, fibromyalgia, and Crohn’s consists of small-N trials with mixed methodology, which floors both evidence quality and translational signal and keeps the overall in the high-40s.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Mu-opioid antagonist (low-dose immunomodulatory use)

A mu-opioid antagonist used at low doses (1.5 to 4.5 mg) for autoimmune and chronic pain conditions; mechanism via transient opioid blockade and TLR4 modulation.

Abstract

Naltrexone ((5alpha)-17-(cyclopropylmethyl)-4,5-epoxy-3,14-dihydroxymorphinan-6-one; CAS 16590-41-3; molecular formula C20H23NO4; molecular weight 341.40) is a long-acting mu-opioid antagonist approved by the FDA in 1984 (ReVia, Vivitrol) for opioid and alcohol use disorders at standard doses (50 mg/day or 380 mg monthly depot). The low-dose application (LDN, 1.5 to 4.5 mg/day) was developed by Bernard Bihari in the 1980s and has been adopted in immunology and chronic pain communities. Mechanism is multifactorial and incompletely characterized: brief, transient mu-opioid antagonism (only 4 to 6 hours per dose) triggers compensatory upregulation of endogenous opioid synthesis and receptor expression, producing a paradoxical increase in opioid-mediated tone over baseline; secondary TLR4 antagonism on microglia attenuates neuroinflammation. Approved indications: opioid and alcohol use disorders (standard dose). Off-label LDN use in multiple sclerosis, Crohn disease, fibromyalgia, complex regional pain syndrome, and Hashimoto thyroiditis is supported by small clinical trials with mixed methodology. Plasma half-life is approximately 4 hours. Used as a research compound for paradoxical opioid pharmacology and neuroimmune modulation.

Read the full monograph

The full reference document covers compound identification, discovery and developmental history, mechanism of action, pharmacokinetics, sourcing and quality verification, and a curated reference list. Embedded inline below; download for offline reading.

KDC-MN-351Open in new tab →

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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.

May 9, 2026
Cyproheptadine

Plain-language summaryIntrigue 56 / 100

Cyproheptadine, sold as Periactin, is a first-generation antihistamine that also potently blocks 5-HT2A and 5-HT2C serotonin receptors. The combination gives it three fairly distinct clinical roles: appetite stimulation (5-HT2C blockade) used in pediatric failure-to-thrive and in cachexia; treatment of serotonin syndrome (5-HT2A blockade rapidly reverses the toxidrome); and migraine prophylaxis. The H1 and anticholinergic activity produces sedation and dry mouth as expected for a first-generation antihistamine. The serotonin syndrome reversal use is the most clinically important and is not interchangeable with other antihistamines. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundNiche research probe

45/100

Old approved antihistamine with genuine 5-HT2 probe value and sole antidote status in serotonin syndrome

Cyproheptadine has been around since 1961. That fact alone shapes how you evaluate it as a research compound. The mechanism, the clinical uses, the pharmacology — all of it is mapped. There’s no meaningful “is this real” question left to ask.

What keeps it relevant is a narrow but genuinely useful set of properties. The dual H1 and 5-HT2A/5-HT2C antagonism profile isn’t something you replicate cleanly with newer, more selective agents. If you need to study the serotonin syndrome reversal mechanism or the appetite-stimulation pathway driven by 5-HT2C blockade, cyproheptadine is the canonical tool. It’s what investigators reach for when they want the combined H1/5-HT2 blockade signal in a single compound. That’s probe value: real, but narrow.

The serotonin syndrome angle is probably the most clinically interesting thing happening with this compound right now. It remains the only compound with a specific pharmacological rationale as an antidote, and as SSRI/SNRI prescriptions have climbed and combinations with triptans, tramadol, and other serotonergic agents become more common, there’s renewed interest in the reversal mechanism. Honest assessment: most of this is clinical pharmacology, not bench discovery. The compound isnt opening new mechanistic territory. Its confirming what we already know.

The post-SSRI sexual dysfunction research angle is newer and more interesting from a bench perspective. 5-HT2A antagonism is one of the proposed interventions for PSSD, and cyproheptadine gets cited in those discussions. But the evidence there is anecdotal-to-preliminary, and more selective 5-HT2A tools like ketanserin or volinanserin exist for investigators who want clean signal without the H1 confound.

What we think: cyproheptadine earns a place in a research library because of what it is, not what it’s becoming. Its differentiation in the serotonin syndrome space is real. Its evidence quality and translational signal are solid by virtue of six decades of clinical use. But its novelty is essentially zero, and the bench-scale questions it can answer are mostly answered. A serious investigator building a new research program in 2025 would reach for this to confirm a mechanism or use it as a comparator, not as the focus of a program.

We stock it because it’s the reference 5-HT2 antagonist antihistamine with an irreplaceable clinical niche. Thats a legitimate reason. Its just not a reason to call it exciting.

Novelty

20

Mechanism promise

38

In-category differentiation

50

Evidence quality

60

Translational signal

65

Research bench value

50

Rationale Novelty is near-floor for a 1961 approved compound with fully mapped pharmacology, but differentiation and bench value score meaningfully higher because the combined H1/5-HT2A/5-HT2C profile is genuinely unique and its role as the only pharmacological serotonin syndrome antidote is uncontested; strong translational and evidence scores reflect 60-plus years of clinical use, not discovery-stage excitement.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

First-generation antihistamine + 5-HT2 antagonist

A piperidine first-generation antihistamine with 5-HT2A and 5-HT2C antagonist activity; used for appetite stimulation, serotonin syndrome reversal, and migraine prophylaxis.

Abstract

Cyproheptadine (4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-methylpiperidine; CAS 129-03-3; molecular formula C21H21N; molecular weight 287.40) is a piperidine first-generation antihistamine with potent 5-HT2A and 5-HT2C antagonist activity, approved by the FDA in 1961 (Periactin). The compound combines H1 antihistamine activity (Ki approximately 1 nM, comparable to diphenhydramine) with strong 5-HT2 antagonism (Ki approximately 1 nM at 5-HT2A); the combined activity drives appetite stimulation (5-HT2C antagonism, the same mechanism as the appetite gain seen with olanzapine and clozapine), serotonin syndrome reversal, and migraine prophylaxis. Plasma half-life is approximately 8 hours. Approved for allergic conditions; off-label use in failure-to-thrive (pediatric appetite stimulation), serotonin syndrome (the only specific antidote besides supportive care), and post-SSRI sexual dysfunction (5-HT2A antagonism). Used as the canonical 5-HT2 antagonist antihistamine in research.

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May 9, 2026
Diphenhydramine

Plain-language summaryIntrigue 50 / 100

Diphenhydramine, sold as Benadryl, is the canonical first-generation antihistamine and the active ingredient in most over-the-counter sleep aids (ZzzQuil, Tylenol PM, Unisom Sleepminis). It blocks H1 receptors for allergy relief but also blocks muscarinic receptors, producing the classic anticholinergic side effect cluster (dry mouth, urinary retention, constipation, confusion). Long-term use, particularly in older adults, has been linked to cognitive impairment and possibly increased dementia risk in observational studies. Newer non-sedating antihistamines like cetirizine or loratadine are preferred for routine allergy control; diphenhydramine remains useful for acute allergic reactions and as an antiemetic. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundEstablished workhorse

30/100

Canonical 1946 sedating antihistamine, well-understood and thoroughly superseded on every therapeutic dimension

Look, diphenhydramine is almost the ideal negative example for what this library is supposed to surface. It was approved in 1946. It’s in Benadryl, ZzzQuil, Tylenol PM, and approximately every OTC sleep product on the drugstore shelf. The mechanism is textbook second-year pharmacology: potent H1 blockade (Ki ~16 nM) combined with broad muscarinic antagonism across M1-M5 (Ki ~70 nM). The sedation is a side effect that got marketed as a feature. Thats not a research hook, thats a liability someone repackaged.

The anticholinergic burden is the most scientifically active conversation around this compound right now, and the news is not good. The BEERS Criteria flag it explicitly as potentially inappropriate in older adults. Long-term use epidemiology associates it with meaningful dementia risk. The Anticholinergic Cognitive Burden scale uses it as a reference entry. So the “interesting” research angle here is essentially “how bad is this for brains” rather than any forward-looking therapeutic story.

On differentiation: second-generation antihistamines (cetirizine, fexofenadine, loratadine) were developed for the specific purpose of removing exactly what makes diphenhydramine problematic. They strip the CNS penetration, reduce the anticholinergic load, and retain the H1 efficacy. In allergy indications, the second-gen compounds are strictly better. Diphenhydramine survives as an OTC sleep aid because sleepiness is the desired endpoint there, not because it’s pharmacologically refined.

We’ll give it credit where it’s due: the evidence base is massive. Multiple approved indications, well-replicated pharmacokinetics (plasma half-life 4-8 hours, reasonable oral bioavailability), a clear human signal for its approved uses. But strong evidence for tired indications isn’t what this library tracks. What we care about is whether a serious investigator should spend time on it, and the answer is almost never unless they’re specifically studying anticholinergic burden mechanisms or running assay comparisons as a reference standard for H1 pharmacology.

The bench utility is real but narrow. It appears in receptor selectivity panels, ACB scoring research, and as a comparator in antihistamine profiling studies. Thats legitimate. It’s not the kind of indispensable probe that defines what’s possible in a research area. It’s more of a known quantity you include in a table to anchor your assay.

Honestly, the score of 30 probably feels generous given how thoroughly this compound has been superseded. The evidence quality axis pulls it up because 75 years of replicated pharmacology is hard to ignore. But novelty at 5 and mechanism at 12 are where the real story lives: this compound solved a problem in 1946 that was solved more elegantly by 1995. Research time is better spent elsewhere.

Novelty

5

Mechanism promise

12

In-category differentiation

20

Evidence quality

75

Translational signal

55

Research bench value

35

Rationale Diphenhydramine scores near-zero on novelty (1946 approval, OTC ubiquity) and mechanism promise (dual H1/muscarinic antagonism, both trivially understood); evidence quality is high but reflects 75 years of boring clinical confirmation, not frontier signal. No structural cap formally applies, but the raw calculation lands at 30 anyway.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

First-generation H1 antihistamine + anticholinergic

An ethanolamine first-generation H1 antihistamine; the canonical sedating antihistamine and OTC sleep aid.

Abstract

Diphenhydramine (2-(diphenylmethoxy)-N,N-dimethylethanamine; CAS 58-73-1; molecular formula C17H21NO; molecular weight 255.36) is an ethanolamine first-generation H1 antihistamine developed at Parke-Davis and approved in 1946. The compound is the canonical sedating H1 blocker (Ki approximately 16 nM) with significant anticholinergic activity (M1-M5 antagonism, Ki approximately 70 nM). The combined activity produces sedation, dry mouth, blurred vision, and confusion (especially in elderly). Plasma half-life is approximately 4 to 8 hours. Approved indications: allergic conditions, motion sickness, parkinsonism, anaphylaxis. OTC sleep aid use in branded products (Tylenol PM, ZzzQuil) is widespread despite limited efficacy and concerning anticholinergic burden in elderly (associated with dementia risk in long-term use per BEERS criteria). The compound has dose-dependent abuse potential at high doses (deliriant effect from anticholinergic activity). Used as the canonical first-generation H1 antihistamine in research.

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May 9, 2026
Loratadine

Plain-language summaryIntrigue 44 / 100

Loratadine, sold as Claritin, is a second-generation antihistamine that is technically a prodrug: most of its clinical effect comes from the active metabolite desloratadine generated by the liver. Like cetirizine it stays largely peripheral, producing allergy relief without significant sedation or anticholinergic effects. It has somewhat lower H1 affinity than cetirizine but a longer duration of action, supporting once-daily dosing. The choice between loratadine, cetirizine, and fexofenadine is largely a matter of individual tolerability and onset preference. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundEstablished workhorse

32/100

Canonical reference antihistamine superseded by its own metabolite; minimal research frontier value

Look, loratadine is Claritin. It’s been on pharmacy shelves since 1993, it’s been OTC since 2002, and if your grandmother has seasonal allergies she probably has a box in her medicine cabinet. That’s not a knock on the compound exactly, but it tells you everything you need to know about its position in a research library built around frontier science.

The mechanism is single-receptor competitive H1 antagonism in the peripheral compartment. That’s it. There’s no dual-target story, no allosteric angle, no novel signaling cascade. The reason it doesn’t make you sleepy is CNS impermeability, which is a pharmacokinetic feature, not a mechanistic surprise. Schering-Plough figured this out thirty years ago and the field hasn’t needed to revisit it since.

What makes the differentiation score particularly bad is that loratadine is a prodrug of desloratadine, which has roughly 250-fold higher H1 affinity (0.4 nM vs. ~100 nM) and a much longer half-life. Clarinex — desloratadine — exists. If you’re running H1 biology and you need a clean peripheral antihistamine probe, theres almost no reason to reach for loratadine over its own active metabolite. Add fexofenadine (P-gp substrate, even cleaner CNS exclusion) and cetirizine (higher affinity, different selectivity profile) and loratadine occupies a pretty awkward middle ground.

Where loratadine earns real credit is in bench value as a reference standard. The abstract correctly identifies it as the canonical non-sedating H1 antihistamine in research. If you’re characterizing a novel compound’s CNS penetration profile, or running histamine challenge experiments with a well-defined comparator, loratadine is a legitimate tool. The evidence quality and translational scores also reflect decades of well-designed trials, regulatory review across multiple jurisdictions, and extensive post-marketing data. That’s real. It’s just not interesting from a discovery standpoint.

We don’t see a novel indication story here that would change the calculus. There’s some scattered literature on mast cell involvement and inflammatory pathways beyond pure H1 blocking, but nothing with the kind of signal that would reframe this as an active frontier target. The CYP3A4/2D6 metabolism and its drug interaction profile are worth noting for stack work, not for discovery research.

Honestly, if loratadine is in your library, it’s there as a control compound and a sourcing sanity check, not because bench scientists are racing to study it. Score reflects that reality.

Novelty

12

Mechanism promise

15

In-category differentiation

12

Evidence quality

75

Translational signal

65

Research bench value

35

Rationale Loratadine’s high evidence and translational scores reflect three decades of solid clinical data, but those scores are offset heavily by near-floor novelty, mechanism, and differentiation: it is a 1993-approved OTC prodrug whose active species (desloratadine) is separately marketed and pharmacologically superior. The calculated overall of 32 lands without a hard cap binding; the score reflects a compound that functions primarily as a negative-control or reference standard rather than a genuine research target.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Second-generation H1 antihistamine (peripheral)

A piperidine second-generation H1 antihistamine; a non-sedating allergy medication and the prodrug of desloratadine.

Abstract

Loratadine (ethyl 4-(8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)-1-piperidinecarboxylate; CAS 79794-75-5; molecular formula C22H23ClN2O2; molecular weight 382.88) is a piperidine second-generation H1 antihistamine developed at Schering-Plough and approved by the FDA in 1993 (Claritin). H1 affinity is approximately 100 nM, lower than cetirizine but with similar peripheral selectivity (minimal CNS penetration). The principal active species is the metabolite desloratadine (formed via CYP3A4 and CYP2D6), which has higher H1 affinity (approximately 0.4 nM) and longer half-life; desloratadine is marketed separately as Clarinex. Plasma half-life of loratadine is approximately 8 hours; desloratadine half-life is approximately 27 hours. Approved indications: allergic rhinitis, urticaria. Sedation incidence is approximately 8 percent (similar to placebo in most trials), the lowest of the second-generation antihistamines. Used as the canonical non-sedating H1 antihistamine in research.

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May 9, 2026
Famotidine

Plain-language summaryIntrigue 48 / 100

Famotidine, sold as Pepcid, is the most prescribed H2 antihistamine for acid-related gastrointestinal conditions. Unlike H1 blockers used for allergies, H2 blockers reduce gastric acid by blocking histamine signaling at parietal cells in the stomach lining. It is widely used for peptic ulcer disease, GERD, and acid-related upper GI symptoms, with a clean safety profile that allowed OTC availability. The compound briefly attracted attention during the COVID-19 pandemic when retrospective data suggested possible benefit, but prospective trials have been mixed and the proposed anti-inflammatory mechanism remains speculative. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundEstablished workhorse

44/100

Canonical H2 antagonist reference compound with limited novel research upside

Look, famotidine is Pepcid. It’s been sitting in medicine cabinets since 1986 and remains one of the most prescribed OTC compounds on the planet. That’s not a knock on it as a drug. It’s a knock on it as a research frontier.

The mechanism is about as lean as it gets: competitive, highly selective H2 receptor antagonism on gastric parietal cells, suppressing histamine-driven acid output with over 1000-fold selectivity versus H1. Clean pharmacology, well-understood kinetics, renal clearance, short half-life. Theres genuinely nothing under the hood here that a serious investigator hasn’t seen in the literature a hundred times.

The COVID-19 chapter is where things got briefly interesting. Observational data from early 2020 suggested that hospitalized patients taking famotidine had better outcomes, and the proposed mechanisms were legitimately novel for the compound: TMPRSS2 inhibition, sigma-1 receptor modulation, anti-inflammatory effects on immune cell H2 receptors. For a moment it looked like an old drug might have a new story. Then the RCTs came in. The Janowitz et al. pilot was underpowered. The PharmaCyte and larger NIH-supported trials were mostly null or inconclusive. The sigma-1 angle is pharmacologically plausible but the binding affinity data is weak and the clinical signal never materialized in a way that replicated. We think the COVID chapter is closed, or at minimum parked until someone does better mechanistic work on the sigma-1 hypothesis specifically.

Where famotidine does retain genuine research value is as a reference compound for histamine biology. It’s the canonical H2 antagonist you reach for when you want to parse H1 versus H2 contributions in immune cell signaling, gastric mucosa work, or histamine-driven inflammatory models. Ranitidine’s withdrawal due to NDMA contamination actually elevated famotidine’s standing here. Cimetidine has significant CYP450 off-target baggage that famotidine largely avoids. So within the H2 class, famotidine is now the default probe, and that matters for labs doing histamine receptor biology.

But none of that changes the fundamental picture: this is a mature, well-characterized, clinically approved compound with minimal unexplored mechanism space. The evidence base for its primary indications is enormous, which pulls evidence and translational scores up, but that strength is also what makes it boring. Investigators already know what it does. The research conversation has mostly moved on to PPI biology, mucosal repair peptides, and microbiome effects of acid suppression, none of which famotidine is particularly useful for probing. It earns its place as a reference standard. It doesn’t earn much else.

Novelty

22

Mechanism promise

23

In-category differentiation

48

Evidence quality

70

Translational signal

63

Research bench value

50

Rationale Famotidine scores low on novelty and mechanism because it is a 40-year-old, single-receptor blocker in a class largely superseded clinically by PPIs; the COVID-19 investigational angle produced mixed RCTs and the speculative sigma-1/TMPRSS2 mechanisms remain unvalidated. Evidence and translational scores are pulled up by its massive primary-indication trial base, keeping the overall in the low-40s without any cap needing to bind.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

H2 receptor antagonist

A second-generation H2 antihistamine; an acid-suppressing agent for peptic ulcers and GERD; investigated for anti-inflammatory and COVID-19 effects.

Abstract

Famotidine (3-({2-[(diaminomethylene)amino]-1,3-thiazol-4-yl}methylsulfanyl)-N-sulfamoyl-propanimidamide; CAS 76824-35-6; molecular formula C8H15N7O2S3; molecular weight 337.45) is a second-generation H2 receptor antagonist developed at Yamanouchi (now Astellas) and approved by the FDA in 1986 (Pepcid). The compound competitively inhibits H2 receptors on gastric parietal cells, reducing histamine-stimulated gastric acid secretion. H2 selectivity over H1 is greater than 1000-fold. Plasma half-life is approximately 2 to 4 hours; renal excretion is the principal clearance pathway. Approved indications: peptic ulcer disease, GERD, Zollinger-Ellison syndrome. The compound attracted attention during the COVID-19 pandemic after observational data suggested possible benefit; randomized controlled trials have produced mixed results, with proposed mechanisms including TMPRSS2 inhibition, sigma-1 modulation, and anti-inflammatory H2 antagonism on immune cells. Used as the canonical H2 antagonist in research.

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May 9, 2026
Sertraline

Plain-language summaryIntrigue 67 / 100

Sertraline (Zoloft) is one of the most widely prescribed psychiatric medications on the planet. Pfizer brought it to market in 1991 as a follow-on to Prozac with a slightly different shape and a slightly different side-effect profile. The main action is the standard SSRI move: block serotonin from being recycled back into the cell that fired it. A small bonus is mild blockade of the dopamine pump, which a few researchers credit with the somewhat brighter subjective profile some patients report compared to other SSRIs. Approved for depression, OCD, panic, PTSD, social anxiety, and premenstrual mood disorder. Generally considered first-line and reasonably well tolerated. Not stocked by Kodiac. This monograph is provided for research and educational reference.

Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.

Our opinion on this compoundEstablished workhorse

45/100

Clinically dominant reference SSRI with exhausted novelty and modest bench utility as a comparator compound

Look, sertraline is probably the most clinically well-validated compound in our library, and thats exactly the problem. When a molecule has been prescribed to tens of millions of people across six approved indications since 1991, the bench science has long since moved on. We’re not here to revisit what we already know about SERT inhibition. Pfizer’s chemists synthesized this in 1977; the basic pharmacology was settled before most active investigators were in graduate school.

The mechanism is nanomolar SERT inhibition (Ki approximately 0.3 nM) with a minor DAT component (Ki approximately 25 nM) that distinguishes it somewhat from the rest of the SSRI class. We think the DAT angle is genuinely the most scientifically interesting thing about sertraline, and it’s mostly a footnote. The 5-HTTLPR literature tried to personalize SSRI prescribing for decades and largely failed; the monoamine hypothesis has taken its share of hits; and anything new you want to ask about SERT biology has better, more selective probes available today. The research conversation has moved toward network-level antidepressant mechanisms, rapid-acting approaches, and psychoplastogens that make single-target reuptake inhibition look like a solved problem.

Where sertraline does hold genuine bench value is as a reference standard. The dichlorophenyl moiety is a frequently-appearing structural feature in SSRI SAR programs, and if you’re running SERT binding assays sertraline is a logical comparator. It’s also a well-characterized positive control in rodent FST and TST models of depression and anxiety, which matters when you want a known-good anchor alongside whatever experimental compound you’re actually studying. That’s real utility, but it’s the utility of a ruler, not the utility of what you’re measuring.

The evidence and translational scores are, honestly, among the highest in the library. Multiple phase 3 RCTs, regulatory approvals across major jurisdictions, replicated over three decades. The irony is that this is precisely why sertraline scores poorly on novelty and mechanism: the literature is exhausted, not exciting. A serious investigator doesn’t wake up thinking they should study sertraline. They wake up thinking they need sertraline as a control condition.

Sourcing is trivial, stability is excellent, the CYP interaction profile is thoroughly mapped (2D6 inhibition present but weaker than fluoxetine or paroxetine), and there are no surprises in handling. None of that makes it a compelling primary research target; it makes it convenient. We score it at 45 because the bench reference value and the sterling clinical record pull it above the floor, but this is not where a serious research program directs its primary attention. Use it as the comparator, not the subject.

Novelty

18

Mechanism promise

22

In-category differentiation

28

Evidence quality

88

Translational signal

82

Research bench value

55

Rationale Stellar evidence and translational scores reflect decades of replicated phase 3 data across six indications, but these are entirely offset by near-zero novelty and mechanism interest; sertraline’s bench value is real but confined to reference-standard roles in SERT binding studies and animal model controls. No structural cap applies.

Editorial commentary from Kodiac biolabs. Not a recommendation, not clinical advice. Research use only.

Selective serotonin reuptake inhibitor

A naphthylamine SSRI with mild dopamine reuptake inhibition; one of the most prescribed psychiatric medications worldwide.

Abstract

Sertraline ((1S,4S)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine; CAS 79617-96-2; molecular formula C17H17Cl2N; molecular weight 306.23) is a tetrahydronaphthalene SSRI synthesized at Pfizer in 1977 and approved by the FDA in 1991 under the trade name Zoloft. SERT affinity is nanomolar (Ki approximately 0.3 nM); the compound exhibits weak dopamine transporter inhibition (Ki approximately 25 nM) that is unusual within the SSRI class and may contribute to a subtly different subjective profile. Plasma half-life is 22 to 36 hours; the principal metabolite N-desmethylsertraline is pharmacologically active but with reduced SERT affinity. Hepatic metabolism is via CYP2B6, CYP2C19, CYP2D6, and CYP3A4; clinically relevant CYP2D6 inhibition exists but is weaker than fluoxetine or paroxetine. Approved indications include major depressive disorder, OCD, panic disorder, PTSD, social anxiety disorder, and premenstrual dysphoric disorder. Used as a reference compound in SERT binding studies and animal models of depression and anxiety; the dichlorophenyl moiety is a target structural feature in numerous SSRI structure-activity relationship studies.

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May 9, 2026

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