Selective Calcitonin Gene-related Peptide Receptor Research Articles

Pharmacologic characterization of atogepant: A potent and selective calcitonin gene-related peptide receptor antagonist.

The trigeminal sensory neuropeptide calcitonin gene-related peptide (CGRP) is identified as an essential element in migraine pathogenesis. In vitro and in vivo studies evaluated pharmacologic properties of the CGRP receptor antagonist atogepant. Radioligand binding using 125I-CGRP and cyclic adenosine monophosphate (cAMP) accumulation assays were conducted in human embryonic kidney 293 cells to assess affinity, functional potency and selectivity. Atogepant in vivo potency was assessed in the rat nitroglycerine model of facial allodynia and primate capsaicin-induced dermal vasodilation (CIDV) pharmacodynamic model. Cerebrospinal fluid/brain penetration and behavioral effects of chronic dosing and upon withdrawal were evaluated in rats. Atogepant exhibited high human CGRP receptor-binding affinity and potently inhibited human α-CGRP-stimulated cAMP responses. Atogepant exhibited significant affinity for the amylin1 receptor but lacked appreciable affinities for adrenomedullin, calcitonin and other known neurotransmitter receptor targets. Atogepant dose-dependently inhibited facial allodynia in the rat nitroglycerine model and produced significant CIDV inhibition in primates. Brain penetration and behavioral/physical signs during chronic dosing and abrupt withdrawal were minimal in rats. Atogepant is a competitive antagonist with high affinity, potency and selectivity for the human CGRP receptor. Atogepant demonstrated a potent, concentration-dependent exposure/efficacy relationship between atogepant plasma concentrations and inhibition of CGRP-dependent effects.

Single‐ and Multiple‐Dose Pharmacokinetics and Tolerability of Telcagepant, an Oral Calcitonin Gene‐Related Peptide Receptor Antagonist, in Adults

Telcagepant is a novel, orally active, and selective calcitonin gene-related peptide receptor antagonist being developed for acute treatment of migraine with and without aura. Three separate clinical studies were conducted to evaluate the pharmacokinetics and tolerability of telcagepant following single oral doses in healthy young and elderly men and women and multiple oral doses in men. Telcagepant was rapidly absorbed with a time to maximum concentration of approximately 1.5 hours. The terminal half-life was approximately 6 hours. A greater than dose-proportional increase was observed in the area under the plasma concentration versus time curve from zero to infinity. Following twice-daily dosing, with each dose separated by 2 hours, steady state was achieved in approximately 3 to 4 days with an accumulation ratio of approximately 2. There were no clinically meaningful pharmacokinetic differences when compared across age and gender. Telcagepant was generally well tolerated up to single doses of 1200 mg and multiple doses of 400 mg twice daily.

Monophosphoryl Lipid A-Induced Delayed Preconditioning in Rat Small Intestine Is Mediated by Calcitonin Gene-Related Peptide

Protective effects of ischemic preconditioning in rat small intestine have been shown to be related to the release of calcitonin gene-related peptide. The purpose of the present study was to explore whether monophosphoryl lipid A participated in the protective process of the delayed ischemic preconditioning in the peripheral vascular bed (the anse intestinalis of rat), and whether endogenous calcitonin gene-related peptide is a mediator in this process. Intestinal ischemia was induced by occlusion of the superior mesenteric artery for 30 min, followed by reperfusion for 60 min. The intestinal lesions were evaluated by the measurement of serum lactate dehydrogenase, myeloperoxidase levels, and small intestine tissue contents of malondialdehyde. In addition, calcitonin gene-related peptide in plasma and superior mesenteric vein effluent were also examined. Pretreatment with monophosphoryl lipid A (500 μg/kg. i.p.) 24 h prior to ischemia-reperfusion significantly alleviated the intestinal tissue histology lesions, decreased serum levels of lactate dehydrogenase, myeloperoxidase, and reduced tissue content of malondialdehyde. Moreover, monophosphoryl lipid A markedly increased plasma concentrations of calcitonin gene-related peptide. Pretreatment with capsaicin, which specifically depletes the neurotransmitter content of sensory nerves or calcitonin gene-related peptide-(8-37), a selective calcitonin gene-related peptide receptor antagonist, inhibited the increased calcitonin gene-related peptide release and subsequently abrogated the protection by monophosphoryl lipid A. In conclusion, monophosphoryl lipid A pharmacologically mimics delayed preconditioning and the protective effects are related to the stimulation of calcitonin gene-related peptide release in rat small intestine.