The selectivity and structural determinants of peptide antagonists at the CGRP receptor of rat, L6 myocytes

Howitt, Stephen G. and Poyner, David (1997). The selectivity and structural determinants of peptide antagonists at the CGRP receptor of rat, L6 myocytes. British Journal of Pharmacology, 121 (5), pp. 1000-1004.

Abstract

1. Potency orders were determined for a series of agonists and antagonists on the calcitonin gene-related peptide (CGRP) receptor of rat L6 myocytes. The agents tested were all shown to have been active against CGRP, amylin or adrenomedullin receptors. 2. AC187 had a PIC50 Of 6.8 ± 0.10, making it 14 fold less potent as an antagonist than CGRP8-37 (PIC50, 7.95 ± 0.14). Amyline8-37 was equipotent to AC187 (PIC50, 6.6 ± 0.16) and CGRP19-37 was a fold less potent than either (pIC50 6.1 ± 0.24). 3. [Ala11]-CGRP8-37 was 6 fold less potent than CGRP8-37, (pIC50 7.13 ± 0.14), whereas [Ala18] CGRP8-37 was approximately equipotent to CGRP8-37 (pIC50, 7.52 ± 0.15). However, [Ala11,Ala18]- CGRP8-37 was over 300 fold less potent than CGRP8-37 (pIC50, 5.30 ± 0.04). 4. [Tyr0]-CGRP28-37, amylin19-37 and adrenomedullin22-52 were inactive as antagonists at concentrations of up to 1 μM. 5. Biotinyl-human α-CGRP was 150 fold less potent than human α-CGRP itself (EC50 values of 48 ± 17 nM and 0.31 ± 0.13 nM, respectively). At 1 μM, [Cys(acetomethoxy)(2'7)]-CGRP was inactive as an agonist. 6. These results confirm a role for Arg11 in maintaining the high affinity binding of CGRP8-37. Arg18 is of less direct significance for high affinity binding, but it may be important in maintaining the amphipathic nature of CGRP and its analogues.

Publication DOI: https://doi.org/10.1038/sj.bjp.0701212
Divisions: Life & Health Sciences > Pharmacy
Life & Health Sciences
Uncontrolled Keywords: amylin antagonists,calcitonin-gene related peptide,CGRP antagonists,CGRP receptors,Pharmacology
Full Text Link: http://www3.interscience.wiley.com/journal/122190935/abstract
Related URLs: http://www.scopus.com/inward/record.url?scp=0030926469&partnerID=8YFLogxK (Scopus URL)
Published Date: 1997-07-15
Authors: Howitt, Stephen G.
Poyner, David ( 0000-0003-1590-112X)

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