28-residue secretin-family neuropeptide and immunomodulator
A 28-amino-acid peptide of the secretin/glucagon family with broad anti-inflammatory and bronchodilator activity, used in CIRS and chronic biotoxin protocols and studied for pulmonary arterial hypertension.
Abstract
Vasoactive Intestinal Peptide (VIP; His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn-NH2; CAS 40077-57-4; molecular formula C147H237N43O43S; molecular weight 3326.81) is a 28-residue C-terminally amidated peptide originally isolated from porcine duodenum by Sami Said and Viktor Mutt in 1970 as a vasodilator and bronchodilator activity. VIP belongs to the secretin/glucagon/PACAP peptide family and signals through the VPAC1 and VPAC2 G-protein-coupled receptors expressed widely on epithelial, endothelial, smooth muscle, and immune cells. The pharmacological signature is broad: vasodilation and bronchodilation through cAMP elevation in vascular and bronchial smooth muscle, anti-inflammatory effects through suppression of pro-inflammatory cytokine production (TNF, IL-6, IL-12) and induction of regulatory T cell phenotypes, and neuroprotective and anti-apoptotic effects in central nervous system tissue. VIP has been extensively studied as a research tool for VPAC receptor pharmacology and explored clinically for indications including pulmonary arterial hypertension (Aviptadil, Phase 3, mixed results; emergency use authorization for COVID-19 ARDS in some jurisdictions), sarcoidosis, asthma, and Sjogren’s syndrome. In integrative medicine and chronic inflammatory response syndrome (CIRS) protocols, VIP is administered as an intranasal spray after Marcons (multiple antibiotic resistant coagulase negative staphylococci) eradication; the protocol was developed by Ritchie Shoemaker and is supported by case-series evidence rather than randomized trials. The compound is not FDA-approved for any chronic indication; intranasal VIP for CIRS is compounded by specialty pharmacies. Plasma half-life is short (less than 2 minutes); the intranasal route provides direct nasal mucosal exposure with limited systemic absorption.
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.
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.
A quinuclidine benzothiophene-2-carboxamide developed at EnVivo and advanced by Forum Pharmaceuticals through two global Phase 3 programs in schizophrenia cognitive impairment and one Phase 3 program in Alzheimer disease, terminated in March 2016 after both Phase 3 schizophrenia trials missed co-primary endpoints and following a September 2015 FDA clinical hold for severe gastrointestinal adverse events.
Abstract
Encenicline (development codes EVP-6124 and MT-4666) is a small-molecule selective partial agonist of the homopentameric alpha-7 subtype of the neuronal nicotinic acetylcholine receptor (alpha-7 nAChR), distinguished from earlier candidates in the class by its high subtype selectivity, the relatively favorable functional intrinsic activity profile (60 to 70 percent of the acetylcholine maximum response in heterologous expression systems), and a clinical development trajectory that reached two global Phase 3 programs in cognitive impairment associated with schizophrenia (CIAS-1 and CIAS-2) and one Phase 3 program in Alzheimer disease (COGNITIV-AD). The compound was originated at EnVivo Pharmaceuticals (later renamed Forum Pharmaceuticals) following the 2008 acquisition of the parent quinuclidine benzothiophene chemistry program from Bayer, and was advanced through Phase 1 first-in-human studies in 2010 to 2012, through positive Phase 2 schizophrenia and Alzheimer disease readouts in 2013 to 2015 with effect sizes of approximately Cohen’s d 0.3 to 0.5 on cognitive composite measures, and into the Phase 3 program from 2014. In September 2015 the United States Food and Drug Administration placed the Phase 3 schizophrenia trials and the Alzheimer disease trial on partial clinical hold following reports of severe gastrointestinal adverse events including nausea, vomiting, and gastrointestinal ulceration in a small fraction of patients; the hold was partially lifted in November 2015 to permit completion of the schizophrenia Phase 3 studies under modified safety protocols. In March 2016 Forum announced that both Phase 3 schizophrenia trials had missed their co-primary cognitive and functional endpoints and the program was discontinued. Forum Pharmaceuticals was wound down in 2016. Encenicline represents the most clinically developed alpha-7 nicotinic partial agonist in cognitive applications and is the principal source of the contemporary scientific assessment that monoselective alpha-7 partial agonism, despite robust preclinical pharmacology and Phase 2 cognitive signals, has not produced clinically meaningful improvement at the registration threshold in the indications studied. The compound remains commercially unavailable but is supplied as a research-grade reagent (greater than 98 percent purity) by multiple chemical suppliers and continues to serve as a reference alpha-7 nicotinic partial agonist for fundamental pharmacology research and for combination-pharmacology investigations. This monograph reviews the chemistry, synthesis, and stereochemistry of encenicline; the receptor pharmacology in molecular and electrophysiological detail; the comprehensive human pharmacokinetic record from single ascending-dose Phase 1 and bioavailability studies; the indication-by-indication clinical evidence base across schizophrenia cognitive impairment, Alzheimer disease, and selected exploratory cognitive endpoints; the reconstitution, sourcing, and stack-interaction considerations for laboratory work; the Phase 3 safety signal and its mechanistic interpretation; and a structured comparative assessment of five alpha-7 nicotinic acetylcholine receptor candidates against encenicline on five competency standards.
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.
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.
Secreted peptide hormone encoded by the Energy Homeostasis Associated (ENHO) gene with endothelial-protective, metabolic-regulatory, and neuroprotective activity
A 76-amino-acid secreted peptide discovered in 2008 by Kumar et al. through liver transcriptomic profiling of melanocortin-3 receptor-deficient mice, encoded by the Energy Homeostasis Associated (Enho) gene, and subsequently characterized as a hepatokine and neuropeptide with roles in endothelial nitric oxide synthase upregulation, glucose and lipid homeostasis, insulin sensitization, neuroprotection in experimental ischemic stroke, and anti-atherosclerotic signaling through the orphan G protein-coupled receptor GPR19 and vascular endothelial growth factor receptor 2.
Abstract
Adropin is a 76-amino-acid secreted peptide encoded by the Energy Homeostasis Associated (Enho) gene, first identified in 2008 by Kumar et al. (Cell Metabolism) through microarray profiling of liver gene expression in melanocortin-3 receptor knockout (Mc3r-/-) mice on a C57BL/6J background [1]. The name derives from the Latin aduro (to set fire to) and pinquis (fat or greasy), reflecting the original observation that hepatic Enho expression is acutely upregulated by short-term high-fat feeding and suppressed in states of diet-induced obesity and prolonged caloric excess. The biologically active secreted domain spans amino acids 34 through 76, with residues 1 through 33 constituting a signal peptide that directs membrane anchoring and extracellular release. Human, mouse, and rat adropin amino acid sequences are 100 percent identical, a degree of conservation unusual among metabolic peptides and suggestive of strong functional constraint across mammalian species. The mature peptide has a molecular weight of approximately 4,499 daltons and functions both as a soluble circulating factor and as a membrane-bound protein facilitating intercellular communication through the Notch signaling pathway in the central nervous system. The biological effects of adropin are mediated principally through two receptor systems: the orphan G protein-coupled receptor 19 (GPR19), which couples to downstream MAPK and Akt signaling cascades in cardiomyocytes and other cell types; and vascular endothelial growth factor receptor 2 (VEGFR2), through which adropin upregulates endothelial nitric oxide synthase (eNOS) expression via the PI3K-Akt and ERK1/2 pathways to promote nitric oxide release, endothelial cell proliferation, migration, and capillary tube formation. Lovren et al. (2010) demonstrated in Circulation that adropin-treated human umbilical vein endothelial cells exhibited enhanced proliferation, migration, and tube formation with reduced permeability and tumor necrosis factor-induced apoptosis [2]. In the original Kumar et al. characterization, transgenic overexpression or systemic adropin treatment in diet-induced obese mice attenuated hepatosteatosis and insulin resistance independently of effects on adiposity or food intake, with adropin regulating expression of hepatic lipogenic genes (fatty acid synthase, stearoyl-CoA desaturase 1) and adipose tissue peroxisome proliferator-activated receptor gamma [1]. Preclinical pharmacology has expanded substantially beyond metabolic endpoints: in experimental ischemic stroke models, synthetic adropin administered intravenously at 900 to 2,700 nmol/kg at the onset of or up to 3 hours after permanent middle cerebral artery occlusion dose-dependently reduced infarct size, blood-brain barrier disruption, tight junction protein degradation, matrix metalloproteinase-9 activity, oxidative stress, and neutrophil infiltration through an eNOS-dependent mechanism, as adropin therapy failed to confer neuroprotection in eNOS-deficient mice [3, 4]. Additional preclinical work has demonstrated anti-atherosclerotic activity through suppression of monocyte-endothelial cell adhesion and smooth muscle cell proliferation [5], preservation of the blood-brain barrier after intracerebral hemorrhage through a Notch1/Hes1 pathway [6], and restoration of cardiac glucose oxidation in pre-diabetic obese mice through modulation of the mitochondrial acetyltransferase GCN5L1 [7]. Clinical studies in humans are predominantly observational: serum adropin levels are consistently and significantly lower in patients with coronary artery disease, acute myocardial infarction, metabolic syndrome, type 2 diabetes mellitus, polycystic ovary syndrome, and obstructive sleep apnea compared to healthy controls, with inverse correlations between adropin concentration and disease severity scores including the SYNTAX score for coronary atherosclerotic burden [8, 9, 10]. A meta-analysis by Zheng et al. (2019) encompassing 7 case-control studies with 525 coronary artery disease patients and 420 controls confirmed the consistent inverse association [8]. No human interventional trials of exogenous adropin administration have been published as of the most recent monograph revision. The compound is available as a synthetic research peptide from multiple suppliers (Phoenix Pharmaceuticals, Bachem, Creative Peptides, GenScript) typically as adropin (34-76), the biologically active fragment, at greater than 95 percent purity by HPLC. This monograph reviews the discovery and gene characterization; the amino acid sequence, structure, and synthesis; the dual-receptor molecular pharmacology through GPR19 and VEGFR2-eNOS; the tissue distribution and nutritional regulation of Enho expression; the preclinical pharmacology across metabolic, cardiovascular, and neurological models; the clinical observational evidence base; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events and safety considerations; and a comparative assessment of five metabolic-regulatory peptide candidates (irisin, FGF21, GDF15, apelin, MOTS-c) against adropin on five competency standards.
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.
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.
Synthetic cardioprotective tetrapeptide bioregulator with epigenetic gene-regulatory and anti-apoptotic activity targeting cardiomyocytes
A synthetic tetrapeptide (H-Ala-Glu-Asp-Arg-OH; AEDR) developed at the Saint Petersburg Institute of Bioregulation and Gerontology as an ultrashort peptide bioregulator with cardioprotective, anti-apoptotic, and epigenetic chromatin-regulatory activity targeting cardiomyocytes, cardiac fibroblasts, and myocardial gene expression programs.
Abstract
Cardiogen (H-Ala-Glu-Asp-Arg-OH; AEDR tetrapeptide; molecular formula C18H31N7O9; molecular weight 489.48 g/mol) is a synthetic tetrapeptide bioregulator developed by Vladimir Khavinson and colleagues at the Saint Petersburg Institute of Bioregulation and Gerontology as the cardiac-specific member of the Khavinson ultrashort peptide bioregulator family [1, 2]. The compound belongs to a class of synthetic two-to-seven-residue peptide sequences modeled on tissue-specific peptide fragments isolated from mammalian organ extracts, and is designated as the cardiovascular system bioregulator within this peptide family. Cardiogen shares the Ala-Glu-Asp tripeptide core with the cortical bioregulator Cortagen (Ala-Glu-Asp-Pro) and the pineal bioregulator Epithalon (Ala-Glu-Asp-Gly), differing from these compounds by the fourth-position arginine residue, a single amino acid substitution that determines cardiac tissue specificity within the Khavinson classification system [3, 4]. The principal molecular mechanism of Cardiogen, characterized through molecular modeling, cell culture, and organotypic myocardial tissue studies, is epigenetic regulation of gene expression through direct interaction of the tetrapeptide with double-stranded DNA in gene promoter regions and with histone proteins (H1, H2B, H3, H4), producing chromatin decondensation and reactivation of transcriptional programs in cardiac cells [5, 6, 7]. The cardioprotective activity, characterized in organotypic myocardial tissue cultures, embryonic fibroblast cultures, and coronary artery ligation animal models, includes stimulation of cardiomyocyte proliferation with concurrent suppression of cardiomyocyte apoptosis through p53 protein downregulation, upregulation of cytoskeletal proteins (actin, vimentin, tubulin) by up to five-fold and nuclear matrix proteins (lamin A, lamin C) by up to 2.5-fold relative to control, preservation of myocardial glycogen stores and cellular energy production structures under ischemic conditions, and a reported threefold reduction in mortality following experimental coronary artery ligation in treated versus control groups [8, 9, 10, 11]. In a separate line of investigation, Cardiogen demonstrated tumor-modifying activity against transplanted M-1 sarcoma in senescent rats, with dose-dependent inhibition of tumor growth mediated by hemorrhagic necrosis and stimulation of tumor cell apoptosis through a vascular mechanism rather than direct cytostatic effect [12]. The compound has been characterized in the context of the senescence-associated secretory phenotype of cardiovascular system cells and inflammaging, with evidence that the AEDR tetrapeptide regulates molecules involved in the inflammatory pathways contributing to age-related cardiovascular decline [13]. No formal pharmacokinetic studies have been published for Cardiogen as the isolated synthetic AEDR tetrapeptide. As a linear tetrapeptide with unprotected termini, the compound is expected to undergo rapid proteolytic degradation by aminopeptidases and carboxypeptidases in plasma and gastrointestinal fluid; however, molecular modeling studies have demonstrated that ultrashort peptides are substrates of the proton-coupled oligopeptide transporter (PEPT1/PEPT2) family carriers, supporting intestinal absorption and cellular uptake through active transport mechanisms [14, 15]. No human clinical trials have been published. The compound is not approved by the United States Food and Drug Administration, the European Medicines Agency, or any major Western regulatory authority. Cardiogen is registered in the Russian Federation as a biologically active additive and is commercially available there in capsule and sublingual formulations. It is supplied internationally as a research-grade lyophilized peptide by multiple peptide synthesis vendors at greater than 95 percent purity by high-performance liquid chromatography. This monograph reviews the chemistry, synthesis, and structural characterization of Cardiogen; the discovery and development history within the Khavinson bioregulatory peptide program; the molecular pharmacology including peptide-DNA binding, histone interaction, and cardiac gene expression modulation; the pharmacokinetic considerations for ultrashort peptides; the preclinical pharmacology across cardiac, inflammatory, and aging cell models; the clinical evidence base (absent); sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signal; and a comparative assessment of five cardioprotective or cardiac-repair peptide candidates (Vesugen, Thymosin beta-4, BPC-157, Cortagen, GHK-Cu) against Cardiogen on five competency standards.
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.
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.
Synthetic immunomodulatory tripeptide bioregulator of thymic origin with epigenetic gene-regulatory and cytoprotective activity
A synthetic tripeptide (L-Glu-L-Asp-L-Pro; EDP) derived from structural analysis of the thymic polypeptide complex Thymalin, developed at the Saint Petersburg Institute of Bioregulation and Gerontology as an ultrashort peptide bioregulator with immunomodulatory, cytoprotective, and epigenetic chromatin-regulatory activity targeting thymic epithelial cells, T-lymphocyte subpopulations, and heat-shock protein gene expression.
Abstract
Crystagen (L-glutamyl-L-aspartyl-L-proline; EDP tripeptide; molecular formula C14H21N3O8; molecular weight 359.33 g/mol) is a synthetic tripeptide bioregulator developed by Vladimir Khavinson and colleagues at the Saint Petersburg Institute of Bioregulation and Gerontology as one of the principal short-peptide bioactive components of Thymalin, a bovine thymus polypeptide extract approved in the Soviet Union and Russian Federation since 1982 for clinical immunocorrection [1, 2]. The compound belongs to the Khavinson class of ultrashort (two to seven residue) peptide bioregulators, a family of synthetic sequences modeled on tissue-specific peptide fragments isolated from organ extracts by acid-pepsin hydrolysis and ultrafiltration, and is designated as the thymic immune system bioregulator within this peptide family. Crystagen shares the Glu-Asp dipeptide core with the bronchial bioregulator Chonluten (Glu-Asp-Gly) and the cortical bioregulator Cortagen (Ala-Glu-Asp-Pro), differing from these compounds by the third-position proline residue and the absence of the N-terminal alanine extension, respectively; the single amino acid substitution at the third position determines tissue specificity within the Khavinson classification [3, 4]. In the Khavinson laboratory internal code system, the compound is designated T-36 [5]. The principal molecular mechanism of Crystagen, characterized through molecular modeling, cell culture, and organotypic tissue studies, is epigenetic regulation of gene expression through direct interaction of the tripeptide with double-stranded DNA in gene promoter regions and with histone proteins (H1, H2B, H3, H4), producing chromatin decondensation and reactivation of age-repressed transcriptional programs in immune cells [6, 7, 8]. The immunomodulatory activity, characterized in thymic cell cultures, splenic organotypic cultures, and in the THP-1 monocyte/macrophage cell line, includes stimulation of T-lymphocyte differentiation with increased CD3+ and CD4+ cell populations, normalization of the CD4+/CD8+ ratio, activation of B-cell immunity in the spleen, suppression of thymocyte apoptosis through p53 downregulation and Ki-67 upregulation, enhancement of normal lymphocyte proliferation with concurrent inhibition of K-562 tumor cell proliferation, and modulation of cytokine expression including interleukin-6 normalization [9, 10, 11, 12]. The cytoprotective profile includes a pronounced upregulation of heat-shock protein gene HSPA1A (encoding HSP-70), with expression increasing approximately 2.2-fold relative to baseline in a study of highly trained female artistic gymnasts receiving Crystagen in combination with other peptide bioregulators, an effect accompanied by reduced incidence of acute respiratory infections during epidemic conditions [13, 14]. In a clinical observational study of elderly patients, oral Crystagen administration normalized immunogram parameters in 82 percent of treated individuals compared to 56 percent in the control group [15]. The geroprotective context for Crystagen derives from the parent compound Thymalin, which in a 266-patient, 6-to-8-year prospective clinical study conducted at the Saint Petersburg Institute of Bioregulation and Gerontology and the Institute of Gerontology of the Ukrainian Academy of Medical Sciences produced a 2.0-to-2.1-fold reduction in mortality rate relative to control, and a 4.1-fold mortality reduction when combined with the pineal peptide Epithalamin [16]. No formal pharmacokinetic studies have been published for Crystagen as the isolated synthetic EDP tripeptide. As a linear tripeptide with unprotected termini, the compound is expected to undergo rapid proteolytic degradation by aminopeptidases and carboxypeptidases in plasma and gastrointestinal fluid; however, molecular modeling studies have demonstrated that ultrashort peptides including EDP are substrates of the proton-coupled oligopeptide transporter (POT) family carriers PEPT1 and PEPT2, supporting intestinal absorption and cellular uptake through active transport mechanisms [17, 18]. The compound is not approved by the United States Food and Drug Administration, the European Medicines Agency, or any major Western regulatory authority. It is not registered as a pharmaceutical product outside the Russian Federation. Crystagen is commercially available in Russia as a dietary supplement in capsule and sublingual formulations and is supplied internationally as a research-grade lyophilized peptide by multiple peptide synthesis vendors at greater than 95 percent purity by high-performance liquid chromatography. This monograph reviews the chemistry, synthesis, and structural characterization of Crystagen; the discovery and development history within the Khavinson bioregulatory peptide program; the molecular pharmacology including peptide-DNA binding, histone interaction, and gene expression modulation; the pharmacokinetic considerations for ultrashort peptides; the preclinical pharmacology across immune, inflammatory, and aging cell models; the clinical evidence base (observational); sourcing and quality verification; reconstitution and handling; stack interactions and combinations; adverse events and safety signal; and a comparative assessment of five immunomodulatory peptide candidates (Thymogen, Vilon, Thymosin alpha-1, Thymulin, Epithalon) against Crystagen on five competency standards.
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.
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.
Synthetic gonadotropin-releasing hormone superagonist nonapeptide with sustained pituitary-gonadal axis suppression through GnRH receptor desensitization and downregulation
A synthetic nonapeptide analog of endogenous gonadotropin-releasing hormone bearing a D-histidine(N-benzyl) substitution at position 6 and an ethylamide C-terminal modification, conferring approximately 100- to 200-fold greater potency than native GnRH and marked resistance to enzymatic degradation, developed at Ortho Pharmaceutical in the early 1980s and now FDA-approved as a once-yearly subcutaneous hydrogel implant for advanced prostate cancer (Vantas, approved 2004, discontinued 2020) and central precocious puberty (Supprelin LA, approved 2007), distinguished from other GnRH agonists by the highest binding affinity in the clinical class and the longest approved dosing interval achieved through a diffusion-controlled hydrogel polymer reservoir delivery system.
Abstract
Histrelin (pGlu-His-Trp-Ser-Tyr-D-His(Bzl)-Leu-Arg-Pro-NHEt; CAS 76712-82-8, free base; molecular formula C66H86N18O12; molecular weight 1323.53) is a synthetic nonapeptide analog of the hypothalamic decapeptide gonadotropin-releasing hormone (GnRH, also designated luteinizing hormone-releasing hormone, LHRH) distinguished from other members of the clinical GnRH agonist class by exceptionally high receptor binding affinity and by a unique formulation as a once-yearly subcutaneous hydrogel polymer implant [1, 2]. The compound incorporates two structural modifications to native GnRH that collectively confer superagonist potency and metabolic stability: replacement of glycine at position 6 with D-histidine bearing an N-benzyl substituent on the imidazole ring, which eliminates the principal endopeptidase cleavage site and introduces a bulky aromatic moiety favorable to hydrophobic interaction with the GnRH receptor transmembrane domain; and replacement of the C-terminal glycinamide (position 10) with an ethylamide, which further resists carboxypeptidase degradation [3, 4]. The resulting peptide binds the type I GnRH receptor with affinity approximately 100- to 200-fold greater than native GnRH and produces the characteristic biphasic pharmacological response common to all GnRH superagonists [5, 6]. Acute administration stimulates pituitary gonadotroph secretion of luteinizing hormone and follicle-stimulating hormone, producing transient elevations in gonadal steroid output (the “flare” phase, lasting 7 to 14 days). Chronic continuous administration produces homologous desensitization of the GnRH receptor through receptor internalization, uncoupling from Gq/11-phospholipase C signaling, and transcriptional downregulation of GnRH receptor expression, resulting in profound and sustained suppression of gonadotropin secretion and a hypogonadal state equivalent to surgical castration in both sexes [5, 6, 7]. Histrelin was initially developed at Ortho Pharmaceutical Corporation (a Johnson and Johnson subsidiary) in the early 1980s and studied in daily subcutaneous injection formulations for central precocious puberty, prostate cancer, and endometriosis [8, 9]. The compound was subsequently reformulated by Roberts Laboratories (later acquired by Shire Pharmaceuticals, then Endo Pharmaceuticals) into a diffusion-controlled hydrogel polymer reservoir subcutaneous implant delivering approximately 65 micrograms of histrelin acetate per day over 12 months [10, 11]. This implant technology produced two FDA-approved products: Vantas (50 mg histrelin acetate implant for palliative treatment of advanced prostate cancer, approved October 2004) and Supprelin LA (50 mg histrelin acetate implant for central precocious puberty, approved May 2007) [12, 13]. Vantas was discontinued in 2020 owing to manufacturing quality issues at the production facility; Supprelin LA remains commercially available. Pharmacokinetics of the implant formulation are characterized by sustained zero-order drug release producing median steady-state serum histrelin concentrations of approximately 0.2 to 0.4 ng/mL, with a terminal elimination half-life of the released peptide of approximately 4 hours, 92 percent subcutaneous bioavailability, and approximately 70 percent plasma protein binding [10, 14]. Metabolism is hepatic through peptidase-mediated degradation. The adverse-event profile is dominated by the pharmacological consequences of gonadal steroid suppression: hot flashes, reduced libido, erectile dysfunction or amenorrhea, and long-term bone mineral density reduction. Implant site reactions (bruising, pain, erythema) occur in approximately 50 percent of recipients. The initial flare phase carries specific risk in metastatic prostate cancer, which is mitigated by co-administration of an antiandrogen during the first 2 to 4 weeks of therapy. Postmarketing surveillance has identified rare but serious adverse events including pseudotumor cerebri, seizures, psychiatric symptoms (emotional lability, depression, suicidal ideation), and severe cutaneous adverse reactions. This monograph reviews the chemistry and synthesis, the biphasic GnRH receptor pharmacology, the comprehensive human pharmacokinetic record, the clinical evidence base across prostate cancer, central precocious puberty, endometriosis, and gender-affirming therapy indications, sourcing and quality verification, reconstitution and handling, stack interactions, adverse-event signal, and a comparative assessment of five GnRH agonist candidates against histrelin on five competency standards.
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.
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.
Endogenous neuropeptide agonist of galanin receptor type 2 (GALR2) and galanin receptor type 3 (GALR3)
A 14-amino-acid C-terminally amidated neuropeptide of the galanin/kisspeptin/spexin superfamily, identified by bioinformatic hidden Markov model screening of the human proteome in 2007 and subsequently characterized as a satiety factor, metabolic regulator, anxiolytic peptide, and antinociceptive agent operating through selective activation of galanin receptor subtypes 2 and 3.
Abstract
Spexin (SPX), also designated neuropeptide Q (NPQ), is a 14-amino-acid peptide hormone encoded by the C12orf39 gene on human chromosome 12 and processed from a 116-amino-acid prepropeptide by dibasic cleavage and C-terminal alpha-amidation [1, 2]. The mature human sequence (NWTPQAMLYLKGAQ-NH2) is perfectly conserved across all mammalian species examined and differs by only one to two residues from teleost orthologs, placing spexin among the most evolutionarily conserved vertebrate peptide hormones [3]. First identified in 2007 by Mirabeau and colleagues through a hidden Markov model algorithm designed to detect novel secreted peptide hormones in the human genome, and first confirmed biochemically in murine esophageal and gastric tissue [1], spexin was subsequently shown to activate galanin receptor type 2 (GALR2) and galanin receptor type 3 (GALR3) with nanomolar potency (EC50 values of approximately 45.7 and 112.2 nM respectively) while showing no measurable activity at galanin receptor type 1 (GALR1) [4, 5]. This receptor selectivity profile distinguishes spexin from galanin itself, which activates all three galanin receptor subtypes, and establishes spexin as a naturally occurring GALR2/GALR3-selective agonist. The peptide is expressed broadly across central and peripheral tissues including the hypothalamus, hippocampus, amygdala, adipose tissue, liver, gastrointestinal tract, pancreas, kidney, heart, ovary, and testis [6, 7]. Functionally, spexin has been characterized as a satiety factor that suppresses food intake in goldfish, zebrafish, and mice through hypothalamic regulation of orexigenic (neuropeptide Y, agouti-related protein) and anorexigenic (proopiomelanocortin, cocaine- and amphetamine-regulated transcript) neuropeptides [8, 9, 10]. In adipose tissue, spexin inhibits long-chain fatty acid uptake into adipocytes and promotes weight loss in diet-induced obese rodents [11]. Circulating spexin concentrations are significantly reduced in human obesity, type 1 diabetes, type 2 diabetes, metabolic syndrome, and polycystic ovary syndrome, establishing the peptide as a candidate biomarker for metabolic dysregulation [12, 13, 14]. Beyond metabolic regulation, spexin-based GALR2-selective agonists produce anxiolytic effects in murine behavioral models [5], and the metabolically stabilized analog LIT-01-144 produces potent non-opioid peripheral antinociception in persistent inflammatory pain through GALR2 activation [15]. In reproductive physiology, spexin inhibits gonadotropin (LH and FSH) synthesis and secretion in multiple vertebrate species and negatively regulates ovarian steroidogenesis [16, 17]. No human clinical trials of exogenous spexin administration have been reported; the compound remains in the preclinical and biomarker research phase. This monograph reviews the chemistry, gene structure, and peptide processing of spexin; the receptor pharmacology and signal transduction through GALR2 and GALR3; the preclinical pharmacology across metabolic, appetite, nociceptive, anxiolytic, reproductive, and cardiovascular domains; the human biomarker and associative clinical evidence; sourcing and handling considerations for research-grade material; analog development for metabolic stability; and a comparative assessment against five related peptide or receptor-targeted candidates on five competency standards.
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.
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.
Methoxyflurane is an early halogenated ether that had a remarkable second life. As a general anesthetic (Penthrane, 1962) it was withdrawn in 1974 after dose-dependent nephrotoxicity was traced to intrarenal defluorination producing high plasma fluoride that blocks ascending-limb chloride transport. Forty years later it returned in a low-dose hand-held inhaler format (Penthrox, the green whistle) for procedural analgesia, approved in Australia and re-approved in the EU and UK in 2018. The 3 mL inhaler dose for fracture reduction or dressing changes delivers fluoride exposures orders of magnitude below the historical nephrotoxic threshold. Mechanism includes the standard volatile anesthetic profile plus pronounced TRPA1 modulation that contributes to the analgesia. A genuinely novel sub-anesthetic application of an old molecule. 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.
Halogenated ether volatile general anesthetic and analgesic
An early halogenated ether withdrawn for nephrotoxicity but reintroduced in low-dose hand-held inhaler format (Penthrox) for procedural analgesia.
Abstract
Methoxyflurane (2,2-dichloro-1,1-difluoroethyl methyl ether; CAS 76-38-0; molecular formula C3H4Cl2F2O; molecular weight 164.97) is a halogenated methyl ethyl ether developed by Ross Terrell in the 1950s and introduced clinically by Abbott in 1962 (Penthrane). The agent was widely used as a general anesthetic through the early 1970s before reports of dose-dependent nephrotoxicity led to withdrawal as a primary anesthetic in 1974 in the United States. The mechanism of methoxyflurane nephrotoxicity is intrarenal defluorination by CYP2E1 producing inorganic fluoride at concentrations sufficient to inhibit ascending limb chloride transport (high-output renal failure with vasopressin-resistant polyuria, the classical methoxyflurane nephropathy). The threshold for clinically apparent renal injury is approximately 50 micromolar plasma fluoride and is exceeded by general anesthetic doses (MAC 0.16 percent for many hours) but not by the brief, low-dose inhaler format reintroduced as Penthrox in Australia and re-approved in the EU and UK in 2018 for procedural analgesia. The Penthrox formulation delivers approximately 3 mL methoxyflurane through a hand-held disposable inhaler (the green whistle), producing analgesia for procedural pain (extremity injuries, dressing changes, fracture reduction) at exposure levels orders of magnitude below the historical nephrotoxic threshold. The blood-gas partition coefficient is 13, the highest in the class, corresponding to slow induction and prolonged emergence; the clinical Penthrox dose is sub-anesthetic and produces only analgesia and mild sedation. Mechanism includes the standard halogenated ether profile plus pronounced TRPA1 modulation contributing to the analgesic phenotype.
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.
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.
A research-grade arginate salt formulation of the pentadecapeptide BPC-157 sequence, formulated for improved aqueous stability and shelf life relative to acetate-salt parent.
Abstract
Pentadeca Arginate (PDA; the pentadecapeptide Gly-Glu-Pro-Pro-Pro-Gly-Lys-Pro-Ala-Asp-Asp-Ala-Gly-Leu-Val formulated as the arginate salt; the underlying peptide is identical to BPC-157, CAS 137525-51-0; molecular formula C62H98N16O22 free peptide; molecular weight 1419.55 free peptide; the arginate salt adds counterions and is formulated for improved stability) is a research-grade alternative formulation of the BPC-157 pentadecapeptide that has emerged in research-grade peptide vendor catalogs in 2023 to 2024 as a stabilized analog. The pharmacological argument is that the arginate counterion improves aqueous solubility and extends shelf life of the lyophilized solid relative to acetate-salt BPC-157, which is the standard formulation; the underlying peptide sequence and pharmacology are identical, and any differences between PDA and BPC-157 in vivo are attributable to formulation rather than to a different molecule. The published preclinical record on the BPC-157 sequence is summarized in the Kodiac BPC-157 monograph (KDC-MN-002): tendon and ligament healing, vascular reorganization, gastrointestinal mucosal protection, dopaminergic system modulation, broad rodent injury-recovery activity, with the limitation that the literature is dominated by the originating Sikiric group at the University of Zagreb. PDA has no independent published preclinical record beyond the parent BPC-157 work; vendor literature emphasizes formulation stability claims rather than novel pharmacology. Investigators should not assume that PDA differs pharmacologically from BPC-157 acetate; the choice between formulations should be made on stability and handling considerations. Reconstitution and dosing follow BPC-157: bacteriostatic water for injection, refrigerated storage of reconstituted solution, parenteral administration at 250 to 500 mcg per dose. The compound is research-grade and not approved by any regulatory authority for human or veterinary use.
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.
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.
Selective alpha-7 nicotinic acetylcholine receptor full agonist
A quinuclidine benzofuran-2-carboxamide developed at Targacept as a selective alpha-7 nicotinic full agonist with a binding affinity of 1.4 nanomolar at the human alpha-7 receptor, advanced through Phase 2 development for cognitive impairment and negative symptoms of schizophrenia with a positive 12-week exploratory trial followed by a negative larger 24-week confirmatory trial, subsequently licensed to Anvylic Therapeutics for Tourette syndrome and other indications.
Abstract
Bradanicline (development codes TC-5619 and ATA-101) is a small-molecule, highly selective full agonist of the homopentameric alpha-7 subtype of the neuronal nicotinic acetylcholine receptor (alpha-7 nAChR), originated at Targacept Pharmaceuticals (Winston-Salem, North Carolina) from a quinuclidine benzofuran-2-carboxamide chemistry program in the mid-2000s and advanced through Phase 1 and Phase 2 clinical development for cognitive impairment associated with schizophrenia. The compound binds the human alpha-7 nicotinic receptor with a Ki of approximately 1.4 nanomolar, slightly higher affinity than encenicline (Ki approximately 4 nanomolar) and substantially higher affinity than tropisetron at the alpha-7 site, and exhibits functional intrinsic activity of approximately 80 to 90 percent of the acetylcholine maximum response in heterologous expression systems, placing it in the high-efficacy stratum of alpha-7 ligands as a full agonist rather than the partial-agonist class that encenicline and tropisetron occupy. The full-agonist intrinsic activity is the principal medicinal-chemistry differentiator of bradanicline within the broader quinuclidine-amide chemical class. Selectivity over alpha-4-beta-2, alpha-3-beta-4, alpha-3-beta-2, and other neuronal nicotinic subtypes is approximately 100-fold or greater. The compound was advanced through an exploratory Phase 2 trial in 185 schizophrenia patients (Lieberman et al. 2013) at 5 milligrams once daily for 12 weeks, with statistically significant improvement on the Groton Maze Learning Task and on the Scale for Assessment of Negative Symptoms compared to placebo, and a statistically significant drug effect on working memory in the tobacco-using subgroup. A larger confirmatory Phase 2 trial (Walling et al. 2016) in 477 schizophrenia outpatients across 64 sites at 5 or 50 milligrams once daily for 24 weeks did not support a benefit on negative or cognitive symptoms compared to placebo. Targacept terminated the cognitive impairment program in 2013 and the compound was subsequently licensed to Catalyst Biosciences and to Anvylic Therapeutics for Tourette syndrome and selected other neurological indications. The compound represents a useful research-clinical reference for the alpha-7 nicotinic full-agonist class and for the assessment of whether higher functional intrinsic activity at the receptor produces greater clinical benefit. Bradanicline did not produce the severe gastrointestinal toxicity that triggered the September 2015 FDA clinical hold on encenicline; the safety profile in Phase 2 was well-tolerated with no clinically noteworthy findings reported. The compound is supplied as a research-grade reagent (greater than 98 percent purity) by multiple chemical suppliers and continues to serve as a reference alpha-7 nicotinic full agonist for fundamental pharmacology research. This monograph reviews the chemistry, synthesis, and stereochemistry of bradanicline; the receptor pharmacology in detail; the human pharmacokinetic record; the indication-by-indication clinical evidence base; and a structured comparative assessment of five alpha-7 nicotinic acetylcholine receptor candidates against bradanicline on five competency standards.
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.
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.
