CGRP receptor

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... 

O Shaughnessy, C. T. and Connor, H. E.. Investigation of the role of tachykinin Nk1, NK2 receptors and CGRP receptors in neurogenic plasma protein extravasation in dura mater, Eur. J. Pharmacol. 1994, 263, 193-198. 

Several lines of investigation have provided evidence to support the theory that CGRP plays a role in migraine. CGRP is the most abundant primary afferent peptide in trigeminal sensory nerves. Since CGRP is one of the most potent vasodilators known and the CGRP receptor is... 

In 1997 scientists from SmithKIine Beecham published a series of quinine analogs as CGRP antagonists (Daines et al.1997, W09709046). These compounds displayed only weak affinities for the human CGRP receptor in the micromolar range and were therefore not of great importance (Daines et al., 1997). 

A major breakthrough in the field was the development of the first highly potent non-peptide CGRP receptor antagonist BIBN-4096BS (Eberlein et al. (Boehringer... 

SmithKIine Beecham is another company with interests in CGRP receptor antagonists and has filed patent applications for two structural classes, the 3,4-dinitrobenzamides (Daines et al., W09809630) and 4-sulfinyl benzanilides (Daines et al., W09856779). 

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). 

Edvinsson, L., Sams, A., Jansen-Olesen, I., Tajti, J., Kane, S.A., Rutledge, R.Z., Koblan, K.S., Hill, R.G., Longmore, J. Characterization of the effects of a non-peptide CGRP receptor antagonist in SK-N-MC cells and isolated human cerebral arteries, Eur. J. Pharmacol. 2001a, 415, 39-44. 

Hasback, P., Sams, A., Schifter, S., Longmore, J., Edvinsson, L. CGRP receptor mediating CGRP-, adrenomedullin- and amylin-induced relaxation in porcine coronary arteries. Characterization with CompoundV (W09811128), a non-peptide antagonist, Br. J. Pharmacol. 2001, 133, 1405-1413. 

Main, M., Brown, J., Brown, S., Fraser, N.J., Foord, S.M. The CGRP receptor can couple via pertussis toxin sensitive and insensitive G proteins, FEBS Letters 1998, 441, 6-10. 

In animals, adrenomedullin dilates resistance vessels in the kidney, brain, lung, hind limbs, and mesentery, resulting in a marked, long-lasting hypotension. The hypotension in turn causes reflex increases in heart rate and cardiac output. Adrenomedullin also acts on the kidneys to increase sodium excretion, and exerts several endocrine effects including inhibition of aldosterone and insulin secretion. Finally it acts on the central nervous system to increase sympathetic outflow. These diverse actions of adrenomedullin are mediated both by CGRP receptors and unique adrenomedullin receptors, the properties of which are incompletely defined. The major second messenger for both receptors is cAMP. 

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.

Hay DL, Conner AC, Howitt SG, Smith DM, Poyner DR. The pharmacology of adrenomedullin receptors and their relationship to CGRP receptors. J Mol Neurosci 2004 22 105-113. 

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... 

Poyner, D. R., Soomets, U., Howitt, S. G., and Langel, U. (1998) Structural determinants for binding to CGRP receptors expressed by human SK-N-MC and Col 29 cells studies with chimeric and other peptides. Br. J. Pharmacol. 124, 1659-1666. 

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