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The pharmacological profile of the enantiomers of the proposed selective dopamine (DA) autoreceptor agonist 3-PPP [3-(3-hydroxyphenyl)-N-n-propylpiperidine] has been studied. In vitro both enantiomers showed weak DA agonistic activity, and (--)-3-PPP some DA antagonistic effect on DA-stimulated adenylate cyclase activity. Both enantiomers in low doses had a similar profile in vivo: Inhibition of locomotor activity of mice and rats, induction of contralateral circling behaviour in 6-hydroxy-DA-lesioned rats and an emetic effect in dogs. At higher doses, differential effects of the enantiomers were found: (+)-3-PPP induced hyperactivity, weak stereotyped behaviour and ipsilateral circling in hemitransected rats. (--)-3-PPP had depressant effects in high doses, inhibited d-amphetamine-induced hyperactivity and d-amphetamine-, methylphenidate- and apomorphine-induced stereotyped licking/biting in rats and antagonized apomorphine-induced emesis in dogs. However, (+)-3-PPP also showed a weak antagonistic activity against d-amphetamine-induced hyperactivity and d-amphetamine- and apomorphine-induced stereotypy in rats and inhibited apomorphine-induced emesis in dogs. It is suggested that both enantiomers have significant effects on postsynaptic DA receptors in high doses: (--)-3-PPP with weak antagonistic activity in some test models and (+)-3-PPP with agonistic and antagonistic effect. Since these effects of (+)-3-PPP were of low intensity at high doses, (+)-3-PPP may be a partial DA agonist at postsynaptic receptors in high doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Different neuroleptics caused dopamine receptor blockade (antagonism against methylphenidate-induced compulsive gnawing) for varying lengths of time. When the receptor blockade had expired, supersensitivity to dopamine agonists (occurrence of apomorphine-induced compulsive gnawing and enhancement of methylphenidate-induced gnawing) developed and persisted for varying periods of time. The degree and duration of supersensitivity was related to the degree and duration of the preceding receptor blockade. Inhibition of catecholamine or 5-HT synthesis had no influence on development of supersensitivity. Stimulation with a dopamine agonist, apomorphine, during the period of the development of supersensitivity did not modify the enhanced receptor supersensitivity. A cholinergic-dopaminergic balance was shown to be involved in the manifestation of compulsive behavior during the supersensitivity phase. Tolerance to the dopamine antagonistic effect of a neuroleptic also developed after a single neuroleptic treatment, most likely due to increased sensitivity of the receptors for the dopamine agonist. It is concluded, that the dopamine receptor blockade induced by a single dose of a neuroleptic agent is a dynamic phenomenon which in the course of time is replaced by an increased sensitivity of the receptors to dopamine agonists. Noradrenergic or 5-HT neuron systems do not seem to be involved in the neuroleptic-induced supersensitivity, whereas a dopaminergic-cholinergic balance is operative in the supersensitivity situation.

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Behavioural effects on dopaminergic transmission of a phenylindane derivative, Lu 19-005 [(+/-)-trans-3-(3,4-dichlorophenyl)-N-methyl-l-indanamine, HCI], with potent inhibitory effect on dopamine (DA), noradrenaline (NA) and serotonin (5-HT) uptake in rats and the effect on DA, NA and 5-HT activity in mice have been studied and compared with those of other known DA, NA and 5-HT uptake inhibitors with different selectivity ratios. Lu 19-005 induced stereotyped behaviour after parenteral and oral administration with a duration of action of more than 24 h. The stereotyped licking and biting induced by Lu 19-005 was antagonized by reserpine and cis(Z)-flupentixol, but not affected by prazosin, p-chlorophenylalanine and alpha-methyl-p-tyrosine pretreatments. Metergoline slightly facilitated the onset of stereotypy. Lower doses of Lu 19-005 induced ipsilateral circling in unilaterally 6-hydroxy-DA-lesioned rats. Finally, Lu 19-005 antagonized the catalepsy induced by perphenazine. In mice, Lu 19-005 potentiated the apomorphine-induced gnawing, reversed tetrabenazine-induced ptosis and potentiated the behavioural effects of 5-HTP within a similar dose range. The effects of Lu 19-005 were compared with those of other reference compounds. Nomifensine had qualitatively similar effects in rats although of much shorter duration. In mice, nomifensine selectively reversed tetrabenazine-induced ptosis. Weaker effects in all test models were found with bupropion, LR 5182 and GBR 13.069, compounds with inhibitory effect on DA and NA uptake. The DA-, NA- and 5-HT-uptake inhibitor diclofensine, however, had no effect in rats except in the 6-hydroxy-DA-circling test and had low potency in mice. The specific 5-HT- and NA-uptake inhibitors citalopram and talsupram, respectively, were ineffective in all rat models.(ABSTRACT TRUNCATED AT 250 WORDS)

Larsen:The neuropharmacological profile of tefludazine, a potential antipsychotic drug with dopamine and serotonin receptor antagonistic effects. Drug Dev. Res. 7:35-47, 1986. The neuropharmacology of tefludazine, a new neuroleptic with phenylindan srrucrure, nas been investigated in comparison with cis(Z)-flupentixol, fluphenazine, haloperidol, methiothepin, thioridazine, and clozapine. Tefludazine showed potent dopamine (DA) antagonistic activity in a broad range of test models in vitro and in vivo in mice, rats, and dogs (receptor binding, antagonism of DA agonist-induced behavior, inhibition of conditioned avoidance, catalepsy, etc.). High oral activity and long duration of action was found. Interestingly, the cataleptogenic potency at the time of peak effect was seven times weaker than the antistereotypic activity, in contrast with that observed with cis(Z)-flupentixol, fluphenazine, and haloperidol. In addition to DA antagonism, tefludazine was equipotent at 5-HT receptors (in vitro receptor binding, 5-HT antagonism in isolated peripheral tissue, cardiovascular 5-HT antagonism, antagonism of Id-HTP-and 5-MeODMT-induced behaviors). No antimuscarinic and low a-adrenoceptor blocking effect was found in pithed rats and in denervated cat nictitating membrane preparation. The DA15-HT activity profile of tefludazine resembled that of methiothepin, which, however, had potent a-adrenoceptor blocking effect. It is concluded that tefludazine has a neuropharmacological profile that should combine antipsychotic potential with lower risk of extrapyramidal symptoms.

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