Enantiomeric N-substituted N-normetazocines: a comparative study of affinities at sigma, PCP, and mu opioid receptors.

The optical antipodes of N-allyl-N-normetazocine (2; SKF 10047, NANM) were the original compounds used for the classification of the sigma receptor as distinct from other receptors such as the PCP (NMDA), opioid, and dopamine receptors. Later studies showed that (+)-N-(dimethylallyl)-N-normetazocine [(+)-4, (+)-pentazocine] was more potent and selective for the sigma receptor. In order to gain additional structure-activity relationship information, several N-substituted N-normetazocine analogs were prepared and evaluated for their sigma-1 ([3H]-(+)-3-PPP or [3H]-(+)-pentazocine), PCP ([3H]TCP), and mu opioid ([3H]DAMGO) receptor binding affinities. (+)-N-Benzyl-N-normetazocine [(+)-10)] possessed subnanomolar affinities for the sigma site, Ki = 0.67. The analog (+)-10 showed greater than 14,000- and 2400-fold selectivity, respectively, for the sigma receptor relative to the PCP and mu opioid receptors. The N-substituted N-normetazocines were enantioselective for the sigma site. The (+)-N-benzyl analog, (+)-10, showed a 55-fold selectivity relative to (-)-10. Analysis of the data also revealed that (+)-normetazocine [(+)-1] [Ki = 30 nM] possessed the highest affinity for the PCP receptor. However, (+)-metazocine [(+)-5] (Ki = 41 nM) was the most selective compound for the PCP receptor relative to the sigma (51-fold) and mu opioid (greater than 200-fold) sites.

Development of behavioral tolerance to delta 9-THC without alteration of cannabinoid receptor binding or mRNA levels in whole brain.

The effect of repetitive administration of delta-9-tetrahydrocannabinol (delta 9-THC) in mice on behavioral and biochemical tolerance was determined in this study. Mice were injected twice daily with 10 mg/kg delta 9-THC for 6.5 days. On day 8, spontaneous activity was assessed or whole-brain homogenates were prepared for the cannabinoid receptor binding and mRNA studies. Although a twenty-sevenfold tolerance to delta 9-THC was observed in the behavioral assay, there was no significant alteration in receptor binding or mRNA levels.

Behavioural effects after cholinergic stimulation of the reticular thalamic nucleus in rats.

This study investigated the functional relationship between the experimentally induced changes in the activity of the cholinergic, muscarinergic system of the rostral area of the nucleus reticularis thalami (TRN) and the motor behaviour. The effect of direct stimulation of the rostral TRN by the cholinergic agonist carbachol on the behaviour of freely moving rats was observed. Unilateral injection of carbachol (0.2-3.2 micrograms/0.5 microliters) into the rostral TRN caused catalepsy which appeared rapidly and was short-lasting. Furthermore, it induced impairment of the performance on the rota rod. Both effects were dose-dependent. The cholinergic antagonist scopolamine (6.66 micrograms) coadministered with the equimolar dose of carbachol (3.2 micrograms) antagonized the effects of carbachol on both behavioural tests. The described effects seem to be cholinergic- and site-specific within the rostral TRN. The present results suggest that activation of the cholinergic, muscarinergic receptors in the rostral TRN modulate the motor function of rats.