Sigma receptor binding affinity and inhibition of apomorphine-induced climbing.

Several relatively selective compounds with affinity for the sigma binding site were assessed for their ability to inhibit apomorphine-induced climbing in the mouse. Although, the majority of compounds inhibited apomorphine-induced climbing, there was no correlation between the ability to inhibit climbing and potency in sigma binding assays using [3H]1,3-di-o-tolylguanidine (DTG) or [3H](+)-pentazocine as ligands. The potency of the compounds to inhibit binding to muscarinic M1 or M2 receptors correlated with the potency to inhibit apomorphine-induced climbing. However, several of the compounds that inhibit climbing had microM affinity at muscarinic receptors. Whether these concentrations were achieved in vivo is unclear. Our data suggest that sigma activity per se is not responsible for inhibition of apomorphine-induced climbing.

In vivo assessment of napamezole, an alpha-2 adrenoceptor antagonist and monoamine re-uptake inhibitor.

Napamezole is an alpha-2 adrenergic receptor antagonist and a selective inhibitor of 5-hydroxytryptamine re-uptake in vitro. In the present study, napamezole was evaluated in vivo for its ability to antagonize alpha-2 adrenergic receptors and to inhibit 5-hydroxytryptamine re-uptake. The alpha-2 blocking activity of napamezole was demonstrated by its ability to: 1) antagonize clonidine-induced antinociception in mice (ED50 value, 36 mg/kg p.o.; 3 mg/kg s.c.); 2) enhance norepinephrine turnover in rat brain (minimum effective dose, 30 mg/kg p.o.); and 3) enhance locus coeruleus neuronal firing (active at doses greater than or equal to 1 mg kg i.v.) and to reverse clonidine-induced suppression of locus coeruleus firing in rats. The rank order of potencies of napamezole and reference alpha-2 antagonists to inhibit clonidine-induced antinociception (based upon s.c. ED50 values) were: idazoxan greater than yohimbine greater than rauwolscine greater than or equal to napamezole greater than tolazoline greater than or equal to piperoxan greater than RS21361. The relative potencies of compounds to enhance alpha-methyltyrosine-induced depletion of forebrain norepinephrine following p.o. administration were: idazoxan = yohimbine greater than mianserin greater than napamezole greater than RS21361. The ability of each of these compounds to enhance alpha-methyltyrosine-induced depletion of rat-forebrain norepinephrine was reversed by the administration of clonidine. These results indicate that napamezole blocks alpha-2 adrenergic receptors in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)