Piperidinyltetralin sigma ligands.

Sigma receptor ligands have been proposed to be potential antipsychotic drugs based on their activity profile in animal behavioral models and their indirect modulation of dopaminergic function. Compound 15 (DuP 734) is a combined antagonist of sigma-1 and serotonin 5HT2 receptors, which has been entered into phase I clinical trials as a potential antipsychotic drug. Tetralins 1 and 2 were prepared to determine whether restriction of the conformation of 15 and its analogs may lead to differences in binding selectivity or in vivo profile. The syntheses and the structure-activity relationships of these compounds are reported herein. A reduced derivative, 14, had high affinity for sigma-1 and serotonin 5HT2 receptors as well as excellent oral activity in some animal antipsychotic models. Furthermore, compound 14 failed to cause catalepsy in the rat up to 90 mg/kg (po).

The 5HT2 antagonist pirenperone reverses disruption of FR-40 by hallucinogenic drugs.

Indolealkylamine and phenethylamine hallucinogens disrupted responding maintained under a fixed-ratio 40 (FR-40) schedule of reinforcement. LSD, DMT, mescaline and DOM produced dose-dependent decreases in number of reinforcers and increases in 10-sec periods of non-responding (pause-intervals). The 5HT agonist quipazine, as well as the LSD congener lisuride, altered response patterns in a similar manner. The effects of these drugs were examined after pretreatment with pirenperone, an antagonist with specificity toward the 5HT2 receptor with reference to the 5HT1 receptor. The dose-response curves for the phenethylamine hallucinogens were shifted significantly to the right and to a greater degree than were those for the indolealkylamine hallucinogens. Pirenperone also antagonized the effects of quipazine to a degree similar to that observed with the phenethylamine-type hallucinogens. Pirenperone did not significantly shift the dose-response pattern to lisuride. These data suggest that the behavioral disruption induced by these hallucinogens and quipazine relates at least in part to an effect on 5HT2 receptors, while the effects of lisuride do not involve a significant interaction at the 5HT2 receptor.

Mescaline elicits behavioral effects in cats by an action at both serotonin and dopamine receptors.

The characteristic behavioral effects of mescaline in cats were nearly completely blocked by pretreatment with low doses of either a specific serotonin antagonist (methysergide) or a dopamine specific antagonist (haloperidol). These blocking effects were not due to non-specific actions, since methysergide did not block the behavioral effects of apomorphine, and haloperidol did not block the behavioral effects of 5-methoxy-N,N-dimethyltryptamine. Thus, it appears that the behavioral effects of mescaline are dependent upon the simultaneous action of the drug at both serotonin and dopamine receptors.

Effect of zotepine on head-twitch induced by L-5-hydroxytryptophan, mescaline and 2,5-dimethoxy-4-methylamphetamine in mice and rats.

The effect of zotepine, a new neuroleptic, on head-twitch induced by L-5-hydroxytryptophan (L-5HTP), mescaline and 2,5-dimethoxy-4-methylamphetamine (DOM) in mice and rats was compared with that of known neuroleptics and the serotonin receptor blocker cyproheptadine. Among the neuroleptics tested, zotepine and haloperidol produced potent inhibitory effects on head-twitch induced by these three drugs. The results indicate that zotepine has a potent anti-hallucinogenic effect.

Neurolepticlike actions of l-methadone: effect on mescaline-induced altered behavior and on tissue levels of mescaline in mice.

Mice were injected ip with either saline, l-methadone (2.5, 5, 20 mg/kg), perphenazine (1, 10, 15 mg/kg), or chlorprothixene (1.25, 2.5, 15 mg/kg) 30 min prior to mescaline-14C (25 mg/kg). Mescaline-induced behavioral changes such as agitation, excitement, slight increase in ventilation, and fright to sound stimuli were prevented by all doses of three drugs, and head-shaking, scratching, and locomotor-increasing effects by 5 and 20 mg/kg methadone and by all doses of both neuroleptics. Catalepticlike state and moderate to marked hypothermia induced by all doses of chlorprothixene, 10 and 15 mg/kg perphenazine, and 20 mg/kg methadone were not reversed by mescaline. Chlorprothixene (all doses), perphenazine (10, 15 mg/kg), and methadone (5, 20 mg/kg) caused marked retention of mescaline and its deaminated metabolite, 3, 4, 5-trimethoxyphenyl acetic acid in both brain and plasma. The fact that relatively higher doses of methadone than neuroleptics are needed to ensure effective antagonism to mescaline action tends to indicate a less specific interaction of the opiate with the neuroleptic/dopamine receptor proposed for central mescaline effects.

6-Hydroxydopamine inhibits some effects of mescaline centrally administered to rabbits.

The narcotic antagonist naloxone does not antagonize antinociception elicited in the rabbit by 100 microgram/kg of mescaline centrally administered, whereas pretreatment with 6-hydroxydopamine (6-OHDA) inhibits this mescaline effect. Stereotyped behavior of rabbits following central mescaline administration is also prevented by 6-hda pretreatment. Since 6-OHDA in known to produce a degeneration of catecholamine containing nerve terminals, a crucial role of catecholamines is suggested in the complex of effects seen in the rabbit after central administration of the hallucinogen.

Synthesis of potential mescaline antagonists.

1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

[Behavioral pharmacology of berberine-type alkaloids. (2) Central depressant effects of tetrahydroberberine (THB) and related compounds].

The behavioral effects of tetrahydroberberine (THB), tetrahydrocoptisine (THC), tetrahydropalmatine (THP) and tetrahydrojateorrhizine (THJ) were compared with those of chlorpromazine (CPZ) and benzodiazepines in mice and rats. Effects of THB were also determined by electroencephalography (EEG) in rabbits. THB was found to pharmacologically exert various actions similar to those of CPZ which is a major tranquilizer, however, the actions of THB were weaker than those of CPZ. Although THB alone did not induce catalepsy, it enhanced the cataleptogenic action of CPZ. At a dose over the effective levels, THB did not lower normal body temperature or induce muscle relaxation and loss of righting reflex. EEG activities in the frontal cortex areas were markedly affected by THB, e.g., fast waves in spontaneous EEG were converted to slow waves. THB and CPZ in a similar manner elicited a sustaining increase in hippocampal afterdischarge, but the action of THB was weaker than that of CPZ. The acute toxicity of THB was lower than that of CPZ and benzodiazepines and the depressant activity of THB almost equalled that of THC and THP, whereas the activity of 1-THB was 1.5 times as great as that of THB. These data indicate that THB, THC and THP may be a new type of tranquilizer.

Beta-adrenergic blocking agents as potent antagonists of mescaline-induced contractions in the rat uterus.

In the isolated rat uterus, mescaline induces contractions that are notably antagonized by catecholamines, by beta-adrenergic stimulants and certain beta-adrenergic blocking agents as well as by chlorpromazine, amitriptyline and methysergide.

Antagonism of d-lysergic acid diethylamide and mescaline by 1-methyl-1, 2, 5, 6-tetrahydropyridine-N, N-diethyl-carboxamide (THPC).

Contractions of sheep umbilical vasculature induced by 5-hydroxytryptamine, mescaline and d-lysergic acid diethylamide (LSD) were antagonized by 1-methyl-1, 2, 5, 6-tetrahydropyridine-N, N-diethyl-carboxamide (THPC) 5 X 10(-4)M. THPC did not block contractile responses to angiotensin. The data are interpreted to support our previous suggestions that certain chemical entities representing portions of the LSD molecule may be effectively studied as antagonists to the hallucinogens. The present data indicate that THPC is a weak 5-hydroxytryptamine receptor antagonist.