Starting from 2-methyl-3-ethyl-lH-4,5,6,7-tetrahydroindol4one 3 we have prepared 2-methyl-3ethyl-5-morpholinoethyl-1H-4,5,6,7-tetmhydroindol4one. (1) and 2-methyl-3-ethyl-5-(4-o-methoxyphenyl-lpiperazinoethyl)-lH-4,5.6,7-tetrahydroindol-4-one (2) as butyrophenone analogues of the neuroleptic molindone. The affinities of these compounds for Dt and D2 dopamine and 5HT2A serotonin receptors were evaluated in vitro. The affinity of 1 for 9 receptors is less than that of molindone (pKi's 6.23 and 7.48 respectively) and that of 2 similar (pKt 7.55). Roth compounds bind to 5HTw receptors, the affinity of 2 being significantly greater than that of molindone (p&Is of 7.04 and 5.85, and PAZ'S of 7.50 and 6.18. respectively).
Several aminoketones possess potent antipsychotic (netuoleptic) activity: molindonet, first marketed in the USA in 1974, has been used in the treatment of schizophrenia and psychosis, but its associated incidence of extrapyramidal side effects (EPS) is significant; the pyrtolo[2,3-glisoquinoline piquindone (Ro 22-1319)2 is an antipsychotic with a low propensity to induce EPS; and haloperidol is the prototype of a group of butyrophenone derivatives with very potent antipsychotic activity, among them the most potent neuroleptics, spiperone and fluanisone, which are 4-amino-pfluorobutyrophenone derivatives. The clinical efficacy of classical antipsychotics in the treatment of schizophrenia and other psychotic disorders is directly related to their ability to block dopamine 9 receptors in the brat@; however, it has been reported that dopamine receptor blockade in the striatum is closely associated with their extrapyramidal side effects m. Furthermore, the classical antipsychotics are ineffective against negative symptoms of schizophrenia such as apathy, motor retardation. flat affectivity and poverty of speech.
Molindoac Piquindone
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