Synthesis of (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)-1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one, a potent and selective orphanin FQ (OFQ) receptor agonist with anxiolytic-like properties

The development of 8-(2,3,3a,4,5,6-hexahydro-1H-phenalenl-yl)-1-phenyl-1,3, 8-triaza-spiro[4.5]decan-4-ones 3 starting from (RS)-s-acenaphten-1-yl-1-ph enyl-1,3,8-triazaspiro[4.5]decan-4-one 1 is reported. The synthesis and the binding affinities at human OFQ and opioid (mu, kappa, delta) receptors of the stereoisomers 3a-f are described. In vitro the most selective compound , (1S,3aS)-8-(2,3,3a,4,5,6-hexahydro-1 H-phenalenl-yl)-1-phenyl-1,3,8-triaz a-spiro[4.5]decan-4-one 3c, was found to act as a full agonist at the OFQ r eceptor in the GTP gamma(35)S binding test. It turned out to be selective v ersus a variety of other neurotransmitter systems. When tested in vivo foll owing intraperitoneal injection, compound 3c was found to decrease neophobi a in a novel environment and to exhibit dose-dependent anxiolytic-like effe cts in the elevated plus-maze procedure, thus confirming the effects observ ed following intracerebroventricular infusion of the OFQ peptide in rat. (C ) 2000 Editions scientifiques et medicales Elsevier SAS.