Designed modification of partial agonist of ORL1 nociceptin receptor for conversion into highly potent antagonist.
Bioorg Med Chem
; 16(5): 2635-44, 2008 Mar 01.
Article
em En
| MEDLINE
| ID: mdl-18068993
ABSTRACT
Nociceptin is an endogenous agonist ligand of the ORL1 (opioid receptor-like 1) receptor, and its antagonist is a potential target of therapeutics for analgesic and antineuropathy drugs. Ac-RYYRIK-NH(2) is a hexapeptide isolated from the peptide library as an antagonist that inhibits the nociceptin activities mediated through ORL1. However, the structural elements required for this antagonist activity are still indeterminate. In the present study, we evaluated the importance of the acetyl-methyl group in receptor binding and activation, examining the peptides acyl-RYYRIK-NH(2), where acyl (R-CO) possesses a series of alkyl groups, R=C(n)H(2n+1) (n=0-5). The isovaleryl derivative with the C(4)H(9) (=(CH(3))(2)CHCH(2)-) group was found to reveal a high receptor-binding affinity and a strong antagonist nature. This peptide achieved a primary goal of eliminating the agonist activity of Ac-RYYRIK-NH(2) and producing pure antagonist activity.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Desenho de Fármacos
/
Receptores Opioides
/
Antagonistas de Entorpecentes
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioorg Med Chem
Ano de publicação:
2008
Tipo de documento:
Article