It is a widely distributed neuropeptide implicated in conditions such as neurogenic inflammation. Ĭalcitonin gene-related peptide (CGRP) is a member of the calcitonin (CT) family of peptides. Partial agonist,~300-fold decrease in potency where measurable CGRP receptor Cos 7 cells (Bailey and Hay, 2006) Cys 2, Cys 7 -CGRP 10-fold decrease in potency CGRP receptor Cos 7 cells (Bailey and Hay, 2006) Residues 1-5 -CGRP6-37 (SH992). Ala 1 -CGRP Threefold decrease in affinity SK-N-MC cells (van Valen et al., 1989) Ala 1 -CGRP 12-fold increase in affinity Rat brain membranes (Dennis et al., 1989) Ala 1 -CGRP 33-fold decrease in affinity L6 myocytes Ala 1 Extension by biotin 150-fold decrease in potency L6 myocytes (Howitt and Poyner, 1997) Asp 3 Coupling to 4 azidoaniline Twofold decrease in affinity Solubilized rat cerebellum (Stangl et al., 1993) Asp Porcine iris ciliary body (Heino et al., 1998) Cys 2, Cys 7 Removal of disulphide No agonist activity Rat atria (Tippins et al., 1986) Cys 2, Cys 7 Removal of disulphide Sixfold reduction in affinity SK-N-MC cells (Lang et al., 2006) Cys 2, Cys 7 cyclo -CGRP Twofold decrease in affinity Rat spleen (Dennis et al., 1989) Cys 2, Cys 7 cyclo -CGRP No agonist activity Guinea pig atria (Dennis et al., 1989) Cys 2, Cys 7 2,7 -CGRP Kd 40 nM~400-fold decrease in affinity. CGRP receptors can influence other signalling pathways and pathway-selective allosteric antagonists may be useful, but more information is needed about the mechanism of action of CGRP to assess the value of this.
Current screens are largely based on measuring CGRP-mediated changes in cAMP. For selectivity at CGRP receptors, it will be necessary to target parts of the receptor influenced by both RAMP1 and CLR.įor the design of radically new antagonists, more structural information on the receptor is needed.
We will discuss how current antagonists have low bioavailability, limiting their use. Readers will gain an overview of how current non-peptide antagonists seem to bind similar epitopes contributed by both calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1), the main CGRP receptor subunits. The clinical ramifications of targeting the CGRP receptor, the profiles of existing antagonists and the requirements for screening new compounds will be discussed. This review summarises knowledge about the structure and signalling properties of the CGRP receptor. The availability of high-affinity, non-peptide antagonists opens the way for trials of these compounds in other conditions where CGRP antagonism might be useful, such as septic shock and inhibition of angiogenesis. All high-affinity analogues showed antagonistic properties with potency similar to CGRP 8-37.Ĭalcitonin gene-related peptide (CGRP) receptor antagonists have recently come to attention with the development of olcegepant and telcagepant for the treatment of migraine. At position 29, a hydrophobic residue is preferred that constricts the secondary structure, whereas position 34 is required to stabilize the conformation of the backbone. The substitution at positions 29 and 34 by turn-inducing amino acid mimetica showed that these turns are highly diverse. We applied it to investigate the predicted turn structures centered at Pro(29) and Pro(34). This tracer was shown to be as potent as commercially available (125)I-tracers for the determination of agonists and to have increased sensitivity for antagonists.
To identify high-affinity antagonists in competitive binding studies, we identified a novel radioactive tracer, -halphaCGRP 8-37, which was labeled in solution by a recently developed strategy using photolabile protecting groups at reactive side chains. Calcitonin gene related peptide (CGRP) plays an important role in the CNS and in the cardiovascular system.
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