2( 3H)-benzoxazolone and 2( 3H)-benzothiazolone derivatives: Novel, potent and selective σ1 receptor ligands

Abstract

A series of original 2( 3H)-benzoxazolone and 2( 3H)-benzothiazolone derivatives were evaluated for their affinity at σ 1 and σ 2 receptor subtypes in competition binding experiments, using [ 3 H ](+)-pentazocine or [ 3 H ]1,3-di- o-tolyl-guanidine (DTG) in the presence of 100 nM (+)- N-allylnormetazocine (NANM) in guinea pig brain membranes. Several of these derivatives showed preferential selectivity for σ 1 binding sites. Compound 1 [3-(1-piperidinoethyl)-6-propylbenzothiazolin-2-one] emerged as a potent σ 1 receptor ligand ( K i=0.6 nM) and displayed a moderate selectivity over the σ 2 receptor subtype ( K i for σ 2/ K i for σ 1=29). Compounds 2 [3-(1-piperidinopropyl)-6-propanoylbenzothiazolin-2-one] and 3 [3-(1-piperidinopropyl)-6-propanoylbenzoxazolin-2-one] still showed rather high affinities for σ 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 σ 2 receptors, respectively. Unlike their potent affinity for σ binding sites, these compounds had negligible affinity for μ-, δ- and κ-opioid receptors, 5-HT 2, dopamine D 2, and muscarinic M 2 receptors. σ Receptor ligands may affect neuronal transmission and display, in animal models, antipsychotic, cognitive, motor, neuroprotective and anticonvulsant activity. Therefore, on the basis of these findings, these novel σ receptor ligands were assayed, in mice, in three tests: maximal electroshock, subcutaneous pentylenetetrazol, and rotarod neurotoxicity. Compound 1, administered intraperitoneally, was the most effective against maximal electroshock-induced seizures and was devoid of significant neurotoxic effects.