2(3H)-BENZOXAZOLONE AND 2(3H)-BENZOTHIAZOLONE DERIVATIVES - NOVEL, POTENT AND SELECTIVE SIGMA(1) RECEPTOR LIGANDS

A series of original 2(3H)-benzoxazolone and 2(3H)-benzothiazolone der ivatives were evaluated for their affinity at sigma(1) and sigma(2) re ceptor subtypes in competition binding experiments, using [H-3](+)-pen tazocine or [H-3]1,3-di-o-tolyl-guanidine (DTG) in the presence of 100 nM (+)-N-allylnormetazocine (NANM) in guinea-pig brain membranes. Sev eral of these derivatives showed preferential selectivity for sigma(1) binding sites. Compound 1 -(1-piperidinoethyl)-6-propylbenzothiazolin -2-one] emerged as a potent sigma(1) receptor ligand (K-i = 0.6 nM) an d displayed a moderate selectivity over the sigma(2) receptor subtype (K-i for sigma(2)/K-i for sigma(1) = 29). Compounds 2 piperidinopropyl )-6-propanoylbenzothiazolin-2-one] and 3 1-piperidinopropyl)-6-propano ylbenzoxazolin-2-one] still showed rather high affinities for sigma(1) binding sites with K-i values of 2.3 and 8.5 nM, respectively. On the contrary, they had 87- and 58-fold less affinity at sigma(2) receptor s, respectively. Unlike their potent affinity for a binding sites, the se compounds had negligible affinity for mu-, delta- and kappa-opioid receptors, 5-HT2, dopamine D-2, and muscarinic M-2 receptors. sigma Re ceptor ligands may affect neuronal transmission and display, in animal models, antipsychotic, cognitive, motor, neuroprotective and anticonv ulsant activity. Therefore, on the basis of these findings, these nove l a receptor ligands were assayed, in mice, in three tests: maximal el ectroshock, subcutaneous pentylenetetrazol and rotarod neurotoxicity. Compound 1, administered intraperitoneally, was the most effective aga inst maximal electroshock-induced seizures and was devoid of significa nt neurotoxic effects. (C) 1997 Elsevier Science B.V.