NDLI: Conformational restraints revealing bioactive β-bend structures for hα CGRP8–37 at the CGRP2 receptor of the rat prostatic vas deferens

Content Provider	PubMed Central
Author	Wisskirchen, F. M. Doyle, P. M. Gough, S. L. Harris, C. J. Marshall, I.
Copyright Year	1999
Abstract	The main aim of this study was to identify putative β-bends and the role of the N- and C-terminus in the CGRP receptor antagonist hα CGRP8–37, which was measured against hα CGRP inhibition of twitch responses in the rat prostatic vas deferens. With a bend-biasing residue (proline) at position 16 in hα CGRP8–37 (10−5 M) an inactive compound was produced, while alanine at the same position retained antagonist activity (apparent pKB 5.6±0.1 at 10−5 M). Proline at position 19 within hα CGRP8–37 (10−5 M) was an antagonist (apparent pKB 5.8±0.1). Incorporation of a bend-forcing structure (beta-turn dipeptide or BTD) at either positions 19,20 or 33,34 in hα CGRP8–37 (10−5 M) antagonized hα CGRP responses (apparent pKB 6.0±0.1 and 6.1±0.1, respectively). Replacement by BTD at both positions 19,20 and 33,34 within hα CGRP8–37 competitively antagonized responses to hα CGRP (pA2 6.2; Schild plot slope 1.0±0.1). Hα CGRP8–37 analogues (10−5 M), substituted at the N-terminus by either glycine8, or des-NH2 valine8 or proline8 were all antagonists against hα CGRP (apparent pKB 6.1±0.1, 6.5±0.1 and 6.1±0.1, respectively), while hα CGRP8–37 (10−5 M) substituted in three places by proline8 and glutamic acid10,14 was inactive. Replacement of the C-terminus by alanine amide37 in hα CGRP8–37 (10−5 M) failed to antagonize hα CGRP responses. Peptidase inhibitors did not alter either the agonist potency of hα CGRP or the antagonist affinities of hα CGRP8–37 BTD19,20 and 33,34 and hα CGRP8–37 Gly8 (against hα CGRP responses). In conclusion, two β-bends at positions 18–21 and 32–35 are compatible with high affinity by BTD and is the first approach of modelling the bioactive structure of hα CGRP8–37. Further, the N-terminus of hα CGRP8–37 is not essential for antagonism, while the C-terminus interacts directly with CGRP receptor binding sites of the rat vas deferens.
Related Links	http://dx.doi.org/10.1038/sj.bjp.0702432
Ending Page	1170
Page Count	8
Starting Page	1163
File Format	PDF
ISSN	00071188
Journal	British Journal of Pharmacology
Issue Number	5
Volume Number	126
Language	English
Publisher Date	1999-03-01
Access Restriction	Open
Subject Keyword	Pharmacology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Pharmacology

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