Use of the butaclamol template in a search for antipsychotic agents with lessened side effects.

A number of molecular similarities between the antipsychotic agents butaclamol and clozapine were noted. Based on the premise that this was a strong indicator of a common mechanism of action (i.e., binding at the antagonist state of the dopamine receptor), a research approach was described. Three simplified analogues (4,8, and 12a) of butaclamol which still retained the molecular functionalities of the parent structure were synthesized and tested in the haloperidol receptor assay. 1-(5-Methyl-10, 11-dihydro-5H-dibenzo[a,d]cycloheptene)-4-tert-butyl-4-piperidine (12a) displaced tritiated haloperidol with an IC50 value of 2.4 nM, as compared to a value of 0.5 nM for butaclamol However, when 12a was tested in vivo or in the spiroperidol receptor assay it was found to be considerably less potent.

Isolation of 10, 11-epoxide of protriptyline in rat urine after protriptyline administration.

The 10, 11-epoxide, 10-hydroxy, and 10, 11-dihydrodiol metabolites of protriptyline were identified in rat urine collected after the administration of 40 mg/kg ip of protriptyline. Mass spectrometric characterization confirmed the structure of these metabolites.

Mass spectrometric identification of 10,11-dihydro-10,11-dihydroxyprotriptyline in rat urine after administration of protriptyline.

10,11-Dihydro-10,11-dihydroxyprotriptyline was identified in rat urine following administration of protriptyline 40 mg kg-1 i.p. Gas chromatographic-mass spectrometric characterization confirmed the structure of this stable metabolite, and its identity with a synthetic sample.