Neuropharmacological profile of EMD 57445, a sigma receptor ligand with potential antipsychotic activity.

EMD 57445 ((S)-(-)-[4-hydroxy-4-(3,4-benzodioxol-5-yl) -piperidin-1-ylmethyl]-3-(4-methoxyphenyl)-oxazolidin- 2-one) is a new sigma receptor ligand with only marginal affinity for many other (including dopamine) receptors. In the present study, central, particularly neuroleptic-like, effects of this compound were evaluated and compared with those of another sigma receptor ligand, rimcazole. EMD 57445 decreased locomotor activity in rats and mice. The amphetamine-induced locomotor hyperactivity and stereotypy were reduced by EMD 57445. The drug was able to inhibit the behavioural effects induced by apomorphine, i.e., the locomotor hyperactivity, stereotypy and aggression in rats, as well as climbing in mice. The hyperlocomotion induced by quinpirole (a dopamine D2/3 receptor agonist) and the grooming induced by SKF 38393 (a dopamine D1 receptor agonist) were decreased by EMD 57445. The behavioural stimulation evoked in rats by non-competitive (MK-801, (+)-5-methyl-10,11-dihydroxy-5H-dibenzo (a,b)-cyclohepten-5,10-imine hydrogen maleate) or competitive (CGP 37849, D,L-E-amino-4-methyl-5-phosphono-3-pentenoic acid) NMDA receptor antagonists was also inhibited. EMD 57445 decreased the cocaine-, morphine- or caffeine-induced locomotor hyperactivity in rats or mice. It neither induced catalepsy nor increased muscle tone in rats. Rimcazole had somewhat different effects: it increased the amphetamine stereotypy as well as the amphetamine-, quinpirole- and cocaine-induced locomotor hyperactivity in rats. The results indicate that EMD 57445 shows functional antidopaminergic activity and may be useful as an antipsychotic drug devoid of extrapyramidal side-effects.

Antiserotonin activity of 9-methyl-2-[3-(4-phenyl-1-piperazinylpropyl)]-1,2,3,4-tetrahydro -beta-carbolin-1-one (B-193).

The effect of B-193 on the central and peripheral serotonin system was studied. B-193 antagonized the head-twitches responses induced by L-5-hydroxytryptophan (L-5-HTP) in mice (ED50 = 0.75 mg/kg ip and 6.6 mg/kg po) and lysergic acid diethylamide (LSD) in rats (ED50 = 1.54 mg/kg ip) and also counteracted forepaws clonic convulsions induced by tryptamine (ED50 = 3.07 mg/kg ip). B-193 (2.5-20 mg/kg ip) antagonized dose-dependently hyperthermia induced by fenfluramine or m-chlorophenylpiperazine (m-CPP) and in a dose of 1 mg/kg iv abolished the stimulation of the flexor reflex evoked by quipazine or fenfluramine. B-193 given in a concentration of 10(-7)-10(-5) mol/l competitively inhibited contractions of the rat stomach fundus strip induced by serotonin (5-HT) (pA2 = 6.5) and the increases in blood pressure induced by 5-HT in pithed rats (ED50 = 0.17 mg/kg iv). In receptor binding studies B-193 has shown distinct affinity to 5-HT2 receptors, and alpha 1-adrenoceptors much weaker affinity to 5-HT1 receptors and alpha 2-adrenoceptors but not to beta-adrenergic, GABA-ergic or benzodiazepine receptors. Our findings demonstrated that B-193 shows potent central and peripheral antiserotonin activity.

Effects of antidepressant drugs, selective noradrenaline-or 5-hydroxytryptamine uptake inhibitors, on apomorphine-induced hypothermia in mice.

Antidepressant drugs which are selective noradrenaline (NA) uptake inhibitors (desipramine, maprotiline, oxaprotiline, talsupram: 0.625-10 mg/kg) antagonized dose-dependently hypothermia induced by 16 mg/kg apomorphine (APO) in mice. Of the two stereoisomers of oxaprotiline, only that inhibiting NA uptake was active. Antidepressants which are selective 5-hydroxytryptamine (5-HT) uptake inhibitors (citalopram, fluvoxamine: 2.5-40 mg/kg) did not affect APO (16 mg/kg)-induced hypothermia. Neither NA nor 5-HT uptake inhibitors counteracted hypothermia induced by 1 mg/kg APO, a dose which is easily antagonized by low doses of dopamine receptor blockers. The antagonistic action of desipramine towards APO (16 mg/kg)-induced hypothermia was prevented by phenoxybenzamine, prazosin and (-)-propranolol, while (+)-propranolol and cyproheptadine were inactive. St. 587 (an alpha 1-adrenoceptor agonist) or salbutamol (an agonist of beta-adrenoceptors) attenuated APO (16 mg/kg)-induced hypothermia: given jointly, the drugs completely reversed it. m-CPP, a 5-HT receptor agonist, did not affect APO (16 mg/kg)-induced hypothermia. In conclusion, the antagonistic action of antidepressant drugs towards APO (16 mg/kg)-induced hypothermia in mice did not reflect their "antidepressant properties", dopamine antagonism or their action on 5-HT receptors, only their effects on the NA uptake and/or NA transmission. Both alpha 1 and beta-adrenoceptors are involved in this antagonistic action.

Ro 11-2465 (cyan-imipramine), citalopram and their N-desmethyl metabolites: effects on the uptake of 5-hydroxytryptamine and noradrenaline in vivo and related pharmacological activities.

Ro 11-2465 (cianopramine, cyan-imipramine) and citalopram (CIT), putative antidepressant drugs, are very potent and selective 5-hydroxytryptamine (5-HT) uptake inhibitors in vitro. This study investigated the effects of these drugs and their desmethyl metabolites, Ro 12-5419 (desmethylcianopramine, cyan-desipramine) and desmethylcitalopram (DCIT), respectively, on the uptake of 5-HT and noradrenaline (NA) in vivo [protection against H 77/77 (4, alpha-dimethyl-metatyramine)-induced displacement of 5-HT and NA] and on related pharmacological activities. All the investigated drugs antagonized H 77/77-induced displacement of 5-HT in the rat brain, though the effects of the metabolites were considerably weaker than those of the parent compounds. The H 77/77-induced displacement of brain NA in rats and mice was antagonized only by Ro 12-5419 and Ro 11-2465. All the drugs potentiated the pressor response to 5-HT in pithed rats; however, Ro 12-5419 and particularly Ro 11-2465 could also block the response when used in higher doses (greater than or equal to 0.1 mg/kg). Only Ro 12-5419 and Ro 11-2465 were able to potentiate the pressor response to NA. Ro 12-5419 also potentiated thyrotropin releasing hormone (TRH) hyperthermia and antagonized reserpine hypothermia in mice; Ro 11-2465 potentiated the TRH hyperthermia only. CIT and DCIT were inactive in both these tests. Of all the four drugs only CIT and Ro 12-5419 considerably stimulated the hind limb flexor reflex in spinal rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Norzimelidine, a metabolite of a highly selective 5-hydroxytryptamine uptake inhibitor, can inhibit the uptake of noradrenaline in-vivo.

Zimelidine and norzimelidine were tested for their ability to counteract reserpine (2.5 mg kg-1)- or apomorphine (1-16 mg kg-1)-induced hypothermia and to potentiate TRH (40 mg kg-1)-induced hyperthermia in mice. Norzimelidine produced positive results in all three tests, behaving like a weak NA uptake inhibitor. Zimelidine was practically inactive. We conclude that the weak inhibitory effect of norzimelidine on the uptake of NA (in-vitro experiments) may be of importance for its pharmacological action and for the clinical action of zimelidine.