TY - JOUR
T1 - Designed modification of partial agonist of ORL1 nociceptin receptor for conversion into highly potent antagonist
AU - Li, Jinglan
AU - Isozaki, Kaname
AU - Okada, Kazushi
AU - Matsushima, Ayami
AU - Nose, Takeru
AU - Costa, Tommaso
AU - Shimohigashi, Yasuyuki
N1 - Funding Information:
This study was supported in part by Health and Labour Sciences Research Grants to Y.S., for Research on the Risk of Chemical Substances, from the Ministry of Health, Labor and Welfare of Japan. This work was also supported in part by Grants-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan to Y.S., and also in part by The Mochida Memorial Foundation for Medical and Pharmaceutical Research to A.M.
PY - 2008/3/1
Y1 - 2008/3/1
N2 - 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-NH2 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-NH2, where acyl (R-CO) possesses a series of alkyl groups, R = CnH2n+1 (n = 0-5). The isovaleryl derivative with the C4H9 (=(CH3)2CHCH2-) 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-NH2 and producing pure antagonist activity.
AB - 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-NH2 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-NH2, where acyl (R-CO) possesses a series of alkyl groups, R = CnH2n+1 (n = 0-5). The isovaleryl derivative with the C4H9 (=(CH3)2CHCH2-) 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-NH2 and producing pure antagonist activity.
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U2 - 10.1016/j.bmc.2007.11.043
DO - 10.1016/j.bmc.2007.11.043
M3 - Article
C2 - 18068993
AN - SCOPUS:40849092954
SN - 0968-0896
VL - 16
SP - 2635
EP - 2644
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 5
ER -