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Structure-activity relationship of [Nphe(1)]-NC-(1-13)-NH2, a pure and selective nociceptin/orphanin FQ receptor antagonist

By R. GUERRINI, CALO' G, BIGONI R, RIZZI D, REGOLI D and SALVADORI S

Abstract

A series of analogs of the ORL1 receptor antagonist\ud [Nphe1]-NC(1-13)-NH2 was prepared and tested for agonistic and\ud antagonistic activities in the mouse vas deferens, a preparation\ud that shows high sensitivity to nociceptin and related peptides.\ud The purpose of this study was to determine the role of the\ud aromatic residue at the N-terminal for antagonism and\ud eventually identify compounds with improved potency. Results\ud indicated that all 23 compounds are inactive as agonists, and\ud the antagonistic potency of the initial template [Nphe1]-\ud NC(1-13)-NH2 is high (pKB 6.43) compared with those of all other\ud compounds except [(S)(bMe)Nphe1]NC(1-13)-NH2 (pKB 6.48). The\ud other 22 compounds can be divided into two groups: 10 show\ud antagonistic potencies (pKB) ranging from 5.30 to 5.86, whereas\ud the other 12 compounds are inactive. This study clearly shows\ud that the aromatic ring of Nphe is very critical for the interaction\ud with the ORL1 receptor and can not be enlarged or sterically\ud modi®ed without signi®cant loss of antagonistic potency

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Year: 2001
OAI identifier: oai:iris.unife.it:11392/470835
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