Calcitonin gene-related peptide CGRP receptors

Merck and Co., Inc., have patented imidazo[4,5-3]pyridines of the general structure 194, which have been found to be antagonists of calcitonin gene-related peptide (CGRP) receptors, which are useful for the treatment of the symptoms for headache, migraine, and cluster headaches <2005W0013894>. Merck have also patented the... 

Daines, R.A., Sham, K.K.C., Tagged, J.J., Kingsbury, W.D., Chan, J., Breen, A., Disa, J., Aiyar, N. Quinine analogs as non-peptide calcitonin gene-related peptide (CGRP) receptor antagonists, Bioorg. Med. Chem. Lett. 1997, 7, 2673-2676. 

Daines, R.A. (SmithKIine Beecham Corporation, USA) Preparation of quinine and quinidine compounds as antagonists of the Calcitonin gene-related Peptide (CGRP) receptor, W09709046 (1997). 

Fig. 17.8 Schematic representation of the PK/PD model. C = model predicted drug concentrations in plasma R = the free form of the calcitonine gene-related peptide (CGRP) receptor R = the blocked form of the CGRP receptor, which has been related to the severity of headache and time to rescue medication using logistic regression and time-to-event analysis.

Woolf CJ, Costigan M (1999) Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci USA 96 7723-7730 Wu D, Doods H, Arndt K, Schindler M (2002) Development and potential of non-peptide antagonists for calcitonin-gene-related peptide (CGRP) receptors evidence for CGRP receptor... 

Calcitonin gene-related peptide (CGRP) receptors... 

The (R)-amino acid, (R)-2-amino-3-(7-methyI-lH-indazoI-5-yI)propanoic acid (R)-108 (Figure 4.30), is a key intermediate for the synthesis of calcitonin gene-related peptide (CGRP) receptors 109 antagonist [135], potentially useful for the treatment of migraine and other maladies [136,137]. 

Figure 4.1. Model of neurogenic inflammation. Stimulation at the skin initiates orthodromic impulses in sensory nerve receptors which elicit antidromic impulses in branching collaterals. The release of neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and somatostatin (SOM) from nerve terminals ensues and they in turn stimulate the release of histamine (H) and the generation of leukotrienes (LT) from nearby mast cells. These mediators then produce vasodilatation and an increase in vascular permeability. In addition, they act on the nerve terminal to produce further...

CALCITONIN GENE-RELATED PEPTIDE RECEPTOR AGONISTS act at a number of related G-protein-coupled receptor subtypes. Human calcitonin gene-related peptide (CGRP) itself, is found in two forms, aCGRP (CGRP-I) and... 

Fig. 5.11 L-Alanine scan of CGRP Y-28-37, a selective antagonist for the human calcitonin gene-related peptide 1 receptor (CGRPi). The analogues were tested In binding-competition assays against ( l-lodohlstldylj-CGRP. Whereas the replacement of some residues...

Finally, cannabinoids inhibit the release of neuropeptides like calcitonin gene-related peptide (CGRP), substance P and somatostatin from sensory neurons (Table 4). Capsaicin or electrical stimulation was used to evoke neuropeptide release. In some of these studies, the endocannabinoid anandamide was used, which has a dual effect on neuropeptide release from sensory neurons. Anandamide possesses an inhibitory effect mediated via CBi receptors at low concentrations and... 

Finally, Zygmunt et al. (1999) described an unusual indirect pathway. They demonstrated that anandamide induces vasorelaxation in rat mesenteric and hepatic arteries, and in guinea pig basilary artery through the activation of TRPVl receptors on sensory neurons, causing the release of the vasodilatory peptide calcitonin gene-related peptide (CGRP) (see also Sect. 4 below, Role of Vanilloid TRPVl Receptors in the Cardiovascular Effects of Cannabinoids ). 

Kruger L, Mantyh PW, Sternine C, Brecha NC, Mantyh CR (1988) Calcitonin gene-related peptide (CGRP) in the rat central nervous system pattern of immunoreactivity and receptor binding sites. Brain Res., 463, 223-244. 

---