The pharmacology of
PD 144418 (1-propyl-5-(3-p-tolyl-isoxazol-5-yl)-1,2,3,6-tetrahydropyridine) was characterized using neurochemical, biochemical and behavioral techniques. For sigma (sigma 1 and sigma 2 respectively) sites,
PD 144418 affinities were determined using whole guinea pig brain membranes with [3H](+)-
pentazocine and
neuroblastoma x
glioma cell membranes using [3H]1,3,di-O-tolylguanidine (DTG) in the presence of 200 nM (+)-
pentazocine.
PD 144418 exhibited an affinity for sigma 1 of 0.08 nM (Ki) versus a K1 of 1377 nM for sigma 2 site. Additional receptor binding studies indicated that
PD 144418 lacked affinity for dopaminergic,
adrenergic,
muscarinic and a variety of other receptors. In vitro studies indicated that
PD 144418 reversed the
N-methyl-D-aspartate (
NMDA)-induced increase in
cyclic GMP (cGMP) in rat cerebellar slices without affecting the basal levels, suggesting that sigma 1 sites may be important in the regulation of
glutamine-induced actions.
PD 144418 potentiated the decrease in
5-hydroxytryptophan caused by
haloperidol in the mesolimbic region, but by itself had no effect in 5-hydroxytrypamine (5-HT) and
dopamine (DA) synthesis. Behaviorally, similar to other sigma
ligands,
PD 144418 antagonized
mescaline-induced scratching at doses that did not alter spontaneous motor activity. This action is suggestive of potential
antipsychotic property. It exhibited no
anxiolytic and
antidepressant properties in the models used. These results show that
PD 144418 is a very selective sigma 1 agent, devoid of any significant affinity for other receptors and that sigma 1 site may modulate actions in the CNS.