Carbetapentane (1, 2-[2-(diethylamino)ethoxy]ethyl 1-phenyl-1-cyclopentanecarboxylate)
binds with high affinity to sigma sites and is a potent antitussive, anticonvulsant,
and spasmolytic agent. However, carbetapentane interacts at muscarinic binding sites
as well, and it is not clear whether either of these receptor systems is involved
in the mechanism(s) of action(s) of this drug. In an attempt to determine whether
these psychoactivities can be attributed to interaction at sigma sites, a series of
carbetapentane analogs were prepared. Phenyl ring substitution; contraction, expansion,
and replacement with a methyl group of the cyclopentyl ring; replacement of the carboxylate
function with an amide, methyl ether, and methylamine; and replacement of the N,N-diethyl
substituent with a morpholino or piperidino moiety were investigated. All of these
novel analogs were evaluated for binding to sigma 1 and sigma 2 sites, and comparison
of binding at muscarinic m1 and m2 and PCP (1-(1-phenylcyclohexyl)piperidine) receptors
was performed. All of the compounds were selective for sigma 1 over sigma 2 sites,
with the three most selective analogs being compounds 34 (65-fold), 35 (78-fold),
and 39 (51-fold). None of the compounds were active at PCP sites, and chemical modification
including (1) replacing the ester function, (2) replacing the cyclopentyl ring with
a smaller ring system (cyclopropyl) or a methyl group, and (3) replacing the diethylamino
moiety with a morpholino group resulted in > 220-fold selectivity over muscarinic
receptor binding. Therefore, several of these novel compounds are potent, sigma 1-selective
ligands which can now be investigated as potential antitussive, anticonvulsant, and
antiischemic agents. These studies may reveal whether sigma 1 sites play a role in
the pharmacological actions of these drugs.