2--hydroxy-5-9-dimethyl-2-allyl-6-7-benzomorphan and levoxadrol

The present study characterized the response of the hypothalamo-pituitary-adrenal axis after the acute administration of enantiomeric pairs of drugs that bind to phencyclidine (PCP) and sigma receptors. Rats were injected with the enantiomers of 1-(1-phenylcyclohexyl)-3-methylpiperidine (PCMP), N-allylnormetazocine (SKF 10,047), dioxadrol (dexoxadrol and levoxadrol) or pentazocine, and plasma levels of adrenocorticotropin (ACTH) and corticosterone were determined by radioimmunoassay. The effects of the enantiomers of PCMP and dioxadrol showed stereospecificity as both (+)-PCMP and dexoxadrol increased plasma levels of ACTH and corticosterone but (-)-PCMP and levoxadrol had no effect. Whereas (-)-pentazocine produced greater responses than (+)-pentazocine, the two enantiomers of SKF 10,047 did not show stereoselectivity. Although the potency of the enantiomers of PCMP and dioxadrol parallel their affinity for binding to PCP receptors, the potency of the enantiomers of pentazocine did not. These results suggest that although the stimulation of the hypothalamo-pituitary-adrenal axis by PCP and drugs with PCP-like activity might be due to interactions with PCP receptors, the effects of pentazocine also involve interactions at other sites.

Topics: Adrenocorticotropic Hormone; Analgesics; Animals; Corticosterone; Dioxolanes; Drug Interactions; Hypothalamo-Hypophyseal System; Injections, Subcutaneous; Male; Phenazocine; Phencyclidine; Piperidines; Pituitary-Adrenal System; Rats; Rats, Sprague-Dawley; Receptors, sigma; Stereoisomerism; Sympathomimetics

The effect of phencyclidine (PCP) on carbachol-induced phosphoinositol hydrolysis was examined in rat brain slices taken from cortex, caudate-putamen and hippocampus. In all three regions studied, PCP significantly inhibited carbachol-induced [3H]inositol phosphate accumulation working as low as 10(-6) M in the cerebral cortex. Because PCP has been shown to act at two sites, a PCP-site and a sigma site, various PCP-like agonists [levoxadrol (Lev), dexoxadrol (Dex) and MK-801 [(+)-5-methyl-10,11-dihydro- 5H-dibenzo(a,b)cyclo-hepaten-5, 10-imine maleate]] as well as sigma agonists [(+)-SKF10047 and 1,3-di(2-toly)guanidine (DTG) were examined for their effects on carbachol-induced phosphoinositol hydrolysis. All but MK-801 significantly inhibited the carbachol action; however, their order of potencies, Lev greater than or equal to Dex much greater than PCP greater than or equal to DTG greater than or equal to (+)-SKF10047 differed from those of other known PCP interactions at PCP and sigma sites. Inasmuch as it is known that PCP competes for binding at muscarinic sites, we examined the effects of PCP, Lev, Dex, DTG and MK-801 on the binding of L-[3H]-3-quinuclidinyl benzilate to its muscarinic site. All blocked L-[3H]-3-quinuclidinyl benzilate binding and exhibited a rank order of potency almost identical to that obtained in the inositol studies with Lev greater than Dex much much greater than DTG much greater than PCP MK-801. In addition, the IC50 values obtained from both studies were very similar. It is concluded that PCP, PCP-like compounds and sigma agonists block carbachol-induced inositol-phosphate accumulation by blockade of muscarinic receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Brain; Carbachol; Culture Techniques; Dibenzocycloheptenes; Dioxolanes; Dizocilpine Maleate; Inositol Phosphates; Male; Phenazocine; Phencyclidine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Muscarinic; Sigma Factor; Transcription Factors

1. Efflux of 86Rb from synaptosomes prepared from rat forebrain was used to assess voltage-gated changes in K+ permeability in mammalian central nerve terminals. 2. Although they are structurally unrelated to phencyclidine (PCP), the sigma-ligands, N-allyl-normetazocine (NANM; SKF 10,047) and cyclazocine, generalize to PCP in behavioral assays, displace [3H]PCP from a high-affinity binding site in brain, and potently block the same voltage-gated K+ channel as PCP itself. 3. The block of the voltage-gated K+ channel in nerve terminals by NANM and cyclazocine was stereoselective and was unaffected by the opioid antagonist naloxone. Moreover, in our experiments the relative activity of the stereoisomers of NANM and cyclazocine compared favourably with their relative activity in behavioural paradigms and binding assays. 4. Dexoxadrol, the D-isomer of dioxodrol, which produces PCP-like behavioural effects and displaces bound [3H]PCP, was a potent blocker of the PCP-sensitive, voltage-gated K+ channel. The corresponding L-isomer, levoxadrol, which produces morphine-like antinociception and sedation, but does not produce PCP-like behaviour nor displace bound [3H]PCP, was a very weak blocker of the voltage-gated K+ channel. 5. Levoxadrol, but not dexoxadrol, activated a separate K+ channel, as manifested by an increase in 86Rb efflux. This effect was blocked by naloxone. 6. We conclude that one of the PCP-sigma-ligand binding sites in the brain may be associated with the voltage-gated, non-inactivating K+ channel we observe in nerve terminals. Our findings are also consistent with the view that some of the behavioural manifestations of PCP intoxication are mediated by block of presynaptic K+ channels.

Topics: Animals; Brain; Cyclazocine; Dioxolanes; Dioxoles; Dose-Response Relationship, Drug; Hallucinogens; In Vitro Techniques; Naloxone; Phenazocine; Phencyclidine; Piperidines; Potassium Channels; Rats; Synaptosomes

The effects of representative drugs from three classes of psychotomimetic compounds (arylcyclohexylamines, benzomorphan opioids and dioxolanes) have been examined on synaptic transmission at an identified monosynaptic pathway in rat hippocampal slices. The compounds tested were phencyclidine (PCP) and ketamine, the racemate and isomers of SKF 10,047 (N-allylnormetazocine), and the isomers of dioxadrol (dexoxadrol and levoxadrol). In the absence of added magnesium ions (Mg) in the perfusion medium low frequency stimulation of the Schaffer collateral-commissural pathway evoked a burst of population spikes in the CA1 cell body region. The secondary components of this response could be abolished by the selective N-methyl-D-aspartate (NMDA) antagonist D-2-amino-5-phosphonovalerate (APV). PCP (1 microM) or ketamine (10 microM) selectively blocked the secondary components of the synaptic response. The effect of PCP was neither mimicked nor prevented by hexamethonium and atropine, phentolamine and propranolol, or clonidine and was therefore unlikely to involve cholinergic or adrenergic neurotransmitter systems. The sigma opiate, (+/-)-SKF 10,047 (10 microM) also abolished selectively the secondary components of the synaptic response. There was no apparent difference between the potency of the stereoisomers of this compound. The action of (+/-)-SKF 10,047 was not affected by either naloxone or haloperidol, indicating that this effect did not involve opioid receptors or the haloperidol-sensitive sigma site. Dexoxadrol (10 microM), but not levoxadrol (10 microM), also selectively blocked the secondary components of the synaptic response. It is concluded that these psychotomimetic agents can block an NMDA receptor-mediated component of synaptic transmission in the hippocampus and that this effect is mediated by a specific PCP/sigma site.

Topics: Analgesics; Animals; Dioxolanes; Hallucinogens; Hippocampus; In Vitro Techniques; Ketamine; Kinetics; Magnesium; Neuromuscular Depolarizing Agents; Phenazocine; Phencyclidine; Piperidines; Rats; Receptors, N-Methyl-D-Aspartate; Receptors, Neurotransmitter; Synapses; Synaptic Transmission