piperidines and 6-(6-(4-hydroxypiperidinyl)hexyloxy)-3-methylflavone-hydrochloride

NPC16377 is a highly selective sigma receptor ligand with low affinity for other neurotransmitter receptors. Preclinical studies indicate that the drug exhibits a pharmacological profile similar to that previously ascribed to atypical antipsychotic drugs. In the present series of experiments, extracellular recording techniques were used to assess the acute effects of NPC16377 on the electrophysiological properties of mesencephalic dopamine-containing neurons in the rat. Systemic administration of NPC16377 produced marginal increases in the firing rate of these neurons but failed to fully reverse the inhibitory effects of the dopamine agonists apomorphine and d-amphetamine. Low doses of the drug potentiated the rate-decreasing effects of d-amphetamine in the substantia nigra but not in the ventral tegmental area. Some of these effects are similar to the actions of atypical antipsychotic drugs, while others appear to be unique to this compound and may involve a direct interaction with sigma sites.

Topics: Action Potentials; Animals; Antipsychotic Agents; Apomorphine; Dextroamphetamine; Dopamine; Flavonoids; Male; Mesencephalon; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma

Sigma receptors have been located in several areas of the brain that control motor function, including on the dopaminergic projections from substantia nigra to striatum. In the current study, the regulation of N-methyl-D-aspartate-stimulated [3H]dopamine release from slices of rat striatum by several sigma ligands has been tested. Both isomers of the benzomorphans SKF10,047 and pentazocine inhibited the stimulated release of dopamine in a concentration-related manner. All these compounds probably activate sigma and non-sigma receptors, including phencyclidine receptors, over the broad concentration ranges tested. However, concentrations of (+)pentazocine below about 100 nM appear to act solely through sigma receptors. This phase of inhibition was reversed by the sigma antagonist N-[-2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-[1- pyrimidinyl-1-piperazine butanol and by the sigma1-selective antagonist (1-(cyclopropylmethyl)-4-2'4"-fluorophenyl)-(2'-oxoethyl)piperi din e HBr. Neither of these antagonists affected stimulated release in the absence of (+)pentazocine. The synthetic sigma ligands 2-(4-morpholino)ethyl 1-phenylcyclohexane-1-carboxylate hydrochloride, 6-[6-(4-hydroxypiperidinyl)-hexoxy]-3-methylflavone hydrochloride and alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1- piperazine butanol enhanced NMDA-stimulated DA release significantly in the presence of (+)pentazocine. These drugs have affinity at non-sigma receptors as well, and their stimulatory effects may be mediated through these receptors along with nonreceptor mechanisms. Our findings on the regulation of dopamine support earlier assertions that sigma receptors may be important in the regulation of motor function.

Topics: Animals; Atropine; Corpus Striatum; Dopamine; Flavonoids; In Vitro Techniques; N-Methylaspartate; Naloxone; Pentazocine; Phenazocine; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI, (NPC 16377), a potent and highly selective sigma-site ligand, was evaluated in tests predictive of antipsychotic and neuroprotective potential and for toxicity. Like haloperidol, clozapine and remoxipride, and the sigma-ligands BMY 14802, ifenprodil and rimcazole, NPC 16377 reversed amphetamine-induced hyperactivity and apomorphine-induced climbing in mice. Additional evidence for antipsychotic activity was obtained in rats with NPC 16377, clozapine, BMY 14802, ifenprodil, haloperidol and rimcazole, all of which reduced conditioned avoidance responses at doses that did not reduce escape behavior. NPC 16377 did not induce catalepsy in mice, suggesting a decreased liability for producing extrapyramidal side effects. NPC 16377 extended survival time for mice exposed to a hypoxic environment. In a model of global ischemia using conscious gerbils, NPC 16377 prevented damage to hippocampal CA1 neurons after either intraperitoneal or oral administration. NPC 16377 did not disrupt prepulse inhibition or block the disruption of prepulse inhibition induced by the phencyclidine site-selective ligand (+)MK-801. In rats trained to discriminate phencyclidine from saline, NPC 16377 did not substitute for the psychotomimetic. These data are consistent with the notion that selective sigma-agents may possess antipsychotic and neuroprotective activities. Moreover, the results from prepulse inhibition and drug discrimination experiments suggest that NPC 16377 is devoid of phencyclidine-like effects.

Topics: Amphetamine; Animals; Antipsychotic Agents; Apomorphine; Avoidance Learning; Brain; Flavonoids; Hypoxia; Lethal Dose 50; Male; Mice; Motor Activity; Nervous System; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma

Certain sigma receptor ligands have been shown to block locomotor stimulation produced by cocaine at doses that do not have significant behavioral activity when given alone. Using a potent and selective ligand of sigma binding sites, 6-[6-(4-hydroxypiperidinyl)hexyloxy]-3-methylflavone (NPC 16377), we further investigated the influence of sigma ligands on additional behavioral and toxic effects of cocaine in mice. A behaviorally inactive dose of NPC 16377 shifted the dose-effect function for the locomotor stimulant effects of cocaine to the right by a factor of 2.5. A higher dose of NPC 16377 produced an insurmountable blockade of this stimulant effect of cocaine. Prior exposure to cocaine enhances the locomotor stimulant effects of cocaine (sensitization). NPC 16377 prevented the development of cocaine sensitization without producing behavioral effects of its own. However, NPC 16377 was unable to block the expression of sensitization in mice previously exposed to cocaine. NPC 16377 also did not consistently alter the discriminative stimulus effects of cocaine or methamphetamine in rats discriminating either 3 or 10 mg/kg of cocaine, or 1 mg/kg of methamphetamine from saline. The potential phencyclidine-like behavioral effects of NPC 16377 were also evaluated. Unlike the NMDA channel ligand, dizocilpine, NPC 16377 did not increase responding under a fixed-interval schedule of food presentation in rats nor did it substitute for the discriminative stimulus effects of either 1.5 mg/kg of phencyclidine or 0.2 mg/kg of dizocilpine in rats discriminating these drugs from saline. NPC 16377 displayed limited but significant anticonvulsant activity against diazepam-sensitive cocaine convulsions. The lethal effects of higher doses of cocaine were neither significantly blocked nor enhanced in rats or mice with NPC 16377. These findings extend earlier observations on the cocaine-blocking effects of sigma ligands to a novel structure with exceptional selectivity for sigma sites. These data indicate that some sigma ligands may be capable of altering certain behavioral and toxic actions of cocaine without notable behavioral side effects as evidenced in preclinical tests. As such, these compounds may ultimately be useful in the treatment of cocaine abuse.

Topics: Animals; Cocaine; Conditioning, Psychological; Discrimination Learning; Flavonoids; Male; Methamphetamine; Mice; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, sigma; Seizures

6-[6-(4-Hydroxypiperidinyl)hexyloxy]-3-methylflavone HCI (NPC 16377), a structurally novel compound, was found to be a highly potent and selective ligand for sigma-sites. Although 5-fold less potent than haloperidol and 2-fold less potent than ifenprodil to inhibit 1,3-di-o-tolylguanidine binding, NPC 16377 (IC50 = 36 nM) was more potent than alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinyl butanol (BMY 14802), rimcazole and the atypical antipsychotic, clozapine. A similar rank order of potency was observed when [3H](+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperdine was used as the radioligand. Like BMY, rimcazole and clozapine, NPC 16377 (IC50 = 2671 nM) had low affinity for dopamine type 2 receptors. Additionally, the compound was only weakly active in 35 additional receptor binding assays including those for serotonin2 and serotonin1C receptors. In vivo, NPC 16377 potently inhibited the binding of [3H]-(+)-N-allylnormetazocine to sigma sites after both intraperitoneal and oral administration. At doses 30-fold in excess of the ID50 to inhibit [3H](+)N-allylnormetazocine, NPC 16377 failed to displace [3H]raclopride from dopamine type 2 binding sites. Unlike haloperidol, BMY 14802, ifenprodil and clozapine, behaviorally effective doses of NPC 16377 did not increase dopamine turnover in the frontal cortex, nucleus accumbens or corpus striatum of rats. In contrast, each of these agents increased circulating levels of both adrenocorticotropin and corticosterone, but only NPC 16377 decreased circulating plasma levels of prolactin. The results of the current study are consistent with the notion that NPC 16377 is a potent, selective and orally active sigma site ligand. At behaviorally relevant doses the compound produces neuroendocrine effects both similar to, and different from, neuroleptics, other sigma-ligands and atypical antipsychotics, while having no effect on dopamine turnover. Given these data, NPC 16377 should prove to be a useful compound to explore further the physiological and functional significance of sigma-sites in brain.

Topics: Adrenocorticotropic Hormone; Animals; Binding Sites; Brain; Corticosterone; Dopamine; Flavonoids; Guinea Pigs; In Vitro Techniques; Ligands; Male; Piperidines; Prolactin; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Receptors, sigma