Target Validation Information
Target ID T32262
Target Name Calcitoningene-related peptide type 1 receptor
Target Type
Clinical Trial
Drug Potency against Target FVATDVGPFAF Drug Info Ki = 8.4 nM [527974]
FVPTDVGAFAF Drug Info Ki = 13.6 nM [527974]
Telcagepant Drug Info IC50 = 10.9 nM [530631]
EPIMER A Drug Info IC50 = 24 nM [530247]
ISOMER A Drug Info IC50 = 6.5 nM [530247]
FVPTDVG-Tic-FAF-Tic Drug Info Ki = 1.8 nM [527974]
Action against Disease Model Telcagepant In vitro, MK-0974 is a potent antagonist of the h uMan (K(i) = 0.77 nM) and rhesus (K(i) = 1.2 nM) CGRP receptors but displays >1500-fold lower affinity for the canine and rat receptors as determined via (125)I-h uMan CGRP competition binding assays. A rhesus pharmacodynamic assay measuring capsaicin-induced changes in forearm dermal blood flow via laser Doppler imaging was utilized to determine the in vivo activity of CGRP receptor antagonism. MK-0974 produced a concentration-dependent inhibition of dermal vasodilation, generated by capsaicin-induced release of endogenous CGRP, with plasma concentrations of 127 and 994 nM required to block 50 and 90% of the blood flow increase, respectively. [552756] Drug Info
The Effect of Target Knockout, Knockdown or Genetic Variations The present study examined whether endogenous CGRP released from neuronal systems facilitates revascularization in response to ischemia using CGRP knockout mice (CGRP-/-). CGRP-/- or their wild-type littermates (CGRP+/+) were subjected to unilateral hindlimb ischemia. CGRP-/- exhibited impaired blood flow recovery from ischemia and decreased capillary density expressed in terms of the n uMber of CD-31-positive cells in the ischemic tissues compared with CGRP+/+. In vivo microscopic studies showed that the functional capillary density in CGRP-/- was reduced. Hindlimb ischemia increased the expression of pro-CGRP mRNA and of CGRP protein in the l uMbar dorsal root ganglia. Lack of CGRP decreased mRNA expression of growth factors, including CD31, vascular endothelial growth factor-A, basic fibroblast growth factor, and transforming growth factor-beta, in the ischemic limb tissue. The application of CGRP enhanced the mRNA expression of CD31 and VEGF-A in h uMan uMbilical vein endothelial cells (HUVECs) and fibroblasts. Subcutaneous infusion of CGRP8-37, a CGRP antagonist, using miniosmotic p uMps delayed angiogenesis and reduced the expression of proangiogenic growth factors during hindlimb ischemia. These results indicate that endogenous CGRP facilitates angiogenesis in response to ischemia. Targeting CGRP may provide a promising approach for controlling angiogenesis related to pathophysiological conditions [527974]
References
Ref 527974J Med Chem. 2006 Jan 26;49(2):616-24.Identification of the key residue of calcitonin gene related peptide (CGRP) 27-37 to obtain antagonists with picomolar affinity at the CGRP receptor.
Ref 527974J Med Chem. 2006 Jan 26;49(2):616-24.Identification of the key residue of calcitonin gene related peptide (CGRP) 27-37 to obtain antagonists with picomolar affinity at the CGRP receptor.
Ref 530631J Pharmacol Exp Ther. 2010 Apr;333(1):152-60. Epub 2010 Jan 11.Pharmacological properties of MK-3207, a potent and orally active calcitonin gene-related peptide receptor antagonist.
Ref 552756Pharmacological characterization of MK-0974 [N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide], a potent and orally active calcitonin gene-related peptide receptor antagonist for the treatment of migraine. J Pharmacol Exp Ther. 2008 Feb;324(2):416-21. Epub 2007 Nov 26.
Ref 530247Bioorg Med Chem Lett. 2009 Aug 15;19(16):4740-2. Epub 2009 Jun 17.The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists.
Ref 530247Bioorg Med Chem Lett. 2009 Aug 15;19(16):4740-2. Epub 2009 Jun 17.The identification of potent, orally bioavailable tricyclic CGRP receptor antagonists.
Ref 527974J Med Chem. 2006 Jan 26;49(2):616-24.Identification of the key residue of calcitonin gene related peptide (CGRP) 27-37 to obtain antagonists with picomolar affinity at the CGRP receptor.

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