Class B G-protein coupled receptors are involved in a wide variety of diseases and are a major focus in drug design. Migraines are a common problem, and one of their major causative agents is the class B G-protein coupled receptor, Calcitonin gene-related peptide (CGRP) receptor, a target for competitive drug discovery. The calcitonin receptor-like receptor generates complexes with a receptor activity-modifying protein, which determines the type of receptor protein formed. The CGRP receptor comprises a complex formed from the calcitonin receptor-like receptor and receptor activity-modifying protein 1. In this study, an in silico docking approach was used to target the calcitonin receptor-like receptor in the bound form with receptor activity-modifying protein 1 (CGRP receptor), as well as in the unbound form. In both cases, the resulting inhibitors bound to the same cavity of the calcitonin receptor-like receptor. The twelve evaluated compounds were competitive inhibitors and showed efficient inhibitory activity against the CGRP receptor and Calcitonin receptor-like receptor. The two studied quinoline derivatives demonstrated potentially ideal inhibitory activity in terms of binding interactions and low range nano-molar inhibition constants. These compounds could prove helpful in designing drugs for the effective treatment of migraines. We propose that quinoline derivatives possess inhibitory activity by disturbing CGRP binding in the trigeminovascular system and may be considered for further preclinical appraisal for the treatment of migraines.

01 May 2008·European Journal of Medicinal ChemistryQ1 · MEDICINE

3D-QSAR studies of triazafluorenone inhibitors of metabotropic glutamate receptor subtype 1

Q1 · MEDICINE

Article

Author: Shyam C. Mallena ; M. Ravi Shashi Nayana ; Y. Nataraja Sekhar ; Madala Kishore Kumar ; Muttineni Ravikumar

Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were developed for 46 triazafluorenone derivatives, inhibiting metabotropic glutamate receptor subtype 1 (mGluR1). It includes molecular field analysis (MFA) and receptor surface analysis (RSA). The QSAR model was developed using 35 compounds and its predictive ability was assessed using a test set of 11 compounds. The predictive 3D-QSAR models have conventional r(2) values of 0.908 and 0.798 for MFA and RSA, respectively; while the cross-validated coefficient r(cv)(2) values of 0.707 and 0.580 for MFA and RSA, respectively. The results of 3D-QSAR methodologies provide a powerful tool directed to the design of novel and selective triazafluorenone inhibitors.

01 Feb 2008·European Journal of PharmacologyQ3 · MEDICINE

Analgesic activity of metabotropic glutamate receptor 1 antagonists on spontaneous post-operative pain in rats

Q3 · MEDICINE

Article

Author: Odile EI-Kouhen ; Gricelda Hernandez ; Donna M. Gauvin ; Andrew O. Stewart ; Renjie Chang ; Scott Baker ; Sonya G. Lehto ; Jorge D. Brioni ; Peter R. Hollingsworth ; Robert B. Moreland ; GuoZhu Zheng ; Prisca Honore ; Chang Z. Zhu

Activation of metabotropic glutamate (mGlu) receptors has previously been shown to play a role in inflammatory or neuropathic pain states. However, the role of mGlu type 1 receptors in post-operative pain remains to be investigated. In the present study, effects of potent and selective mGlu1 receptor antagonists A-841720, A-794282, A-794278, and A-850002 were evaluated in a skin incision-induced post-operative pain model in rats. Post-operative pain was examined 2 h following surgery using weight-bearing difference between injured and uninjured paws as a measure of spontaneous pain. In this model, A-841720, A-794282, A-794278, and A-850002 induced significant attenuation of spontaneous post-operative pain behavior, with ED50s of 10, 50, 50, and 65 micromol/kg i.p., respectively. Depending on the compound, significant motor side effects were also observed at 3 to 10 fold higher doses. These results support the notion that mGlu1 receptor activation plays a significant role in nociceptive transmission in post-operative pain, though motor impairment may be a limiting factor in developing mGlu1 receptor antagonists as novel analgesics.

100 Deals associated with A-794282

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Indication	Highest Phase	Country/Location	Organization	Date
Pain, Postoperative	Preclinical	United States	Abbott Laboratories	13 Nov 2007

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