Synthesis and pharmacological evaluation of 1,2-dihydrospiro[isoquinoline-4(3H),4'-piperidin]-3-ones as nociceptin receptor agonists.
Some synthesized 1,2-dihydrospiro[isoquinoline-4(3 H),4'-piperidin]-3-ones were evaluated as ligands for nociceptin receptor (NOP receptor). Their affinity was established by binding studies, and efficacy was investigated by GTP binding experiments. Selectivity toward DOP, KOP, and MOP receptors was assessed, and structural requirements affecting affinity and selectivity were remarked. Most notably, compound 6d displayed nanomolar NOP receptor affinity and showed more than 800-fold selectivity. The new structures exerted full or partial agonistic activity.
Mustazza
Carlo
C
Dipartimento del Farmaco, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Roma, Italy. carlo.mustazza@iss.it
Borioni
Anna
A
Sestili
Isabella
I
Sbraccia
Maria
M
Rodomonte
Andrea
A
Del Giudice
Maria Rosaria
MR
D002460:Cell Line; D003510:Cyclohexanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011869:Radioligand Assay; D011957:Receptors, Opioid / Q000819:agonists*; D013141:Spiro Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D003510:Cyclohexanes; D007546:Isoquinolines; D010880:Piperidines; D011957:Receptors, Opioid; D013141:Spiro Compounds; D000094942:Nociceptin Receptor; C000722283:OPRL1 protein, human