1: Eur J Pharmacol 1997 Sep 24;335(2-3):267-73
2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives: novel, potent
and selective sigma1 receptor ligands.
Ucar H, Cacciaguerra S, Spampinato S, Van derpoorten K, Isa M, Kanyonyo
M, Poupaert JH
Unite de Chimie Pharmaceutique et de Radiopharmacie, Ecole de Pharmacie,
Universite catholique de Louvain, Brussels, Belgium. ucar@cmfa.ucl.ac.be
A series of original 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives
were evaluated for their affinity at sigma1 and sigma2 receptor subtypes
in competition binding experiments, using [3H](+)-pentazocine or [3H]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 sigma1 binding sites. Compound 1 [3-(1-piperidinoethyl)-6-propylbenzothiazolin-2-one]
emerged as a potent sigma1 receptor ligand (Ki = 0.6 nM) and displayed
a moderate selectivity over the sigma2 receptor subtype (Ki for sigma2/Ki
for sigma1 = 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 sigma1 binding sites with Ki values of 2.3 and
8.5 nM, respectively. On the contrary, they had 87- and 58-fold less affinity
at sigma2 receptors, respectively. Unlike their potent affinity for sigma
binding sites, these compounds had negligible affinity for mu-, delta-
and kappa-opioid receptors, 5-HT2, dopamine D2, and muscarinic M2 receptors.
Sigma 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
sigma 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.
PMID: 9369382, UI: 98034315