GB-115

GB-115 (N-(6-phenylhexanoyl)-glycyl-L-tryptophan amide; CAS 678996-63-9) is a synthetic retrodipeptide analogue of the endogenous anxiogenic tetrapeptide cholecystokinin-4 (CCK-4, Trp-Met-Asp-Phe-NH2), designed and synthesized at the V.V. Zakusov Research Institute of Pharmacology (Russian Academy of Medical Sciences) using the topochemical Shemyakin-Ovchinnikov-Ivanov principle for rational peptide drug design. The compound functions as a selective antagonist of the central cholecystokinin type 1 (CCK-1) receptor, producing anxiolytic activity in rodent and primate behavioral models at doses of 0.05 to 0.2 mg/kg without the sedation, tolerance, dependence, or cognitive impairment associated with benzodiazepine anxiolytics. The biologically active conformation of GB-115 has been identified by nuclear Overhauser effect NMR spectroscopy as a type II beta-turn, with the native spatial distance between the phenyl and indolyl hydrophobic pharmacophores critical for receptor interaction. Structure-activity relationship studies demonstrated that L-tryptophan-containing derivatives produce anxiolytic effects, while D-tryptophan-containing enantiomers produce anxiogenic effects mirroring CCK-4 itself, confirming the stereospecificity of the CCK-1 receptor interaction.

Preclinical pharmacology extends beyond anxiolysis. GB-115 potentiates morphine-induced analgesia through supraspinal opioidergic mechanisms and produces independent antinociceptive activity in chemical and thermal pain models with a significant non-opioid component. Anti-inflammatory effects have been demonstrated in concanavalin A-induced and carrageenan-induced inflammation models and in experimental autoimmune encephalomyelitis in C57Bl/6 mice, where intraperitoneal administration at 1 mg/kg significantly alleviated pathological symptoms, promoted thymus weight recovery, and reduced perivascular edema and neutrophil infiltration of brain tissue. Immunomodulatory activity includes stimulation of phagocytic activity of peritoneal macrophages and humoral immune response in intact mice and immunocorrecting effects in animals with secondary immunodeficiency. The compound reverses antinociceptive tolerance to morphine on sub-chronic co-administration, a property consistent with its CCK-1 receptor antagonist mechanism given the established role of cholecystokinin in opioid tolerance.

Pharmacokinetics are characterized by rapid oral absorption, low absolute bioavailability (approximately 4.65 percent in animal models), and a short elimination half-life of approximately 1.0 hour in humans. The amide bond confers greater peptidase resistance than native peptide bonds, extending plasma detection time relative to unmodified dipeptides. Acute toxicity is very low, with an oral LD50 exceeding 6000 mg/kg in rodents, providing a therapeutic index of approximately 30,000 to 60,000 relative to the effective anxiolytic dose range.

Clinical evaluation has progressed through Phase 2 and Phase 3 trials. An open-label pilot study in 25 patients with generalized anxiety disorder demonstrated significant reduction in Hamilton Anxiety Rating Scale (HAM-A) total scores from a median of 22 at baseline to 5 at day 21 on 6 mg oral dosing (p < 0.001), with concurrent improvement in cognitive processing speed, attention, and reaction time, and no stimulation-related adverse events. A Phase 3 double-blind, randomized, placebo-controlled, multicenter trial (NCT05586789) in 220 patients with anxiety associated with neurasthenia and adjustment disorders confirmed superiority of Ranquilon 6 mg over placebo in reducing anxiety, with all recorded adverse events classified as mild and no serious adverse events or treatment discontinuations. A Phase 4 open-label comparative trial (NCT06843044) against fabomotizole (Afobazole) 30 mg is currently recruiting. This monograph reviews the chemistry, design rationale, and stereochemistry of GB-115; the CCK-1 receptor antagonist mechanism and downstream pharmacology; the preclinical evidence across anxiolytic, analgesic, anti-inflammatory, and immunomodulatory applications; the clinical evidence base including Phase 2 and Phase 3 data; pharmacokinetics across species; sourcing and quality verification; reconstitution and handling; stack interactions; adverse events and safety; and a comparative assessment of five anxiolytic or CCK-modulating alternatives against GB-115 on five competency standards.