Novel non-peptide nociceptin/orphanin FQ receptor agonist, 1-[1-(1-Methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole: design, synthesis, and structure-activity relationship of oral receptor occupancy in the brain for orally potent antianxiety drug.
An endogenous heptadecapeptide, nociceptin/orphanin FQ (N/OFQ), and a G-protein-coupled receptor, N/OFQ peptide (NOP) receptor [or opioid-receptor-like-1 (ORL1) receptor], have been described in terms of its structure, distribution, and pharmacology. Thus, the N/OFQ and NOP receptor are located in the central nervous systems in humans, primates, and rodents, and are involved in the integration of the emotional components in the brain; e.g., N/OFQ displays anxiolytic activity in the brain. For identifying orally potent anxiolytic, drug-design studies were performed with a series of 1,2-disubstituted benzimidazole derivatives, which resulted in the identification of various chemotypes of highly potent NOP selective full agonists in vitro with high or moderate NOP receptor occupancy in the mice brain per os such as 1-[1-(1-methylcyclooctyl)-4-piperidinyl]-2-[(3R)-3-piperidinyl]-1H-benzimidazole 1 (MCOPPB), the most potent novel non-peptide NOP full agonist in vitro and an orally potent anxiolytic in the mice.
Hayashi
Shigeo
S
Pfizer Global Research & Development Nagoya Laboratories, Pfizer Japan Inc., 5-2 Taketoyo, Aichi 470-2393, Japan. Shigeo_Hayashi@nifty.com
Hirao
Akiko
A
Imai
Aki
A
Nakamura
Hiroshi
H
Murata
Yoshinori
Y
Ohashi
Katsuyo
K
Nakata
Eriko
E
D000284:Administration, Oral; D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D001562:Benzimidazoles / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D008297:Male; D010880:Piperidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
C528441:1-(1-(1-methylcyclooctyl)-4-piperidinyl)-2-((3R)-3-piperidinyl)-1H-benzimidazole; D014151:Anti-Anxiety Agents; D001562:Benzimidazoles; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor