octoclothepine--(s)-isomer and tefludazine

Representatives of the phenylindan, -indene, and -indole classes of compounds (3-6) have been tested for affinity for the dopamine D-1 and D-2 receptors. The compounds all display high affinities for these receptors. Conformational analysis using MM2(87) and subsequent molecular least-squares superimpositions have been performed in order to determine if the affinities of the compounds can be rationalized by a recently proposed dopamine D-2 receptor-interaction model. In spite of the different geometric and conformational properties, the compounds can be well accommodated into the model in their calculated lowest energy conformations. The molecular superimpositions allow the absolute configurations of the active enantiomers of 4 and 5 to be predicted. The present structure-activity study extends the receptor-interaction model by suggesting that the receptor is not very sensitive to the orientation of the p-fluorophenyl ring in 1 and 3-6 or to the exact spatial location of the associated fluoro substituent.

Topics: Animals; Chemical Phenomena; Chemistry, Physical; Computer Simulation; Dopamine D2 Receptor Antagonists; Indans; Indenes; Indoles; Molecular Conformation; Molecular Structure; Piperazines; Rats; Receptors, Dopamine D1; Structure-Activity Relationship

Conformational analysis with molecular mechanics (MM2(85] and molecular superimposition studies of (1R,3S)-(+)- and (1S,3R)-(-)-4-[3-(4-fluorophenyl)-6-(trifluoromethyl)indan-1-yl]-1- piperazineethanol (tefludazine) and (S)-(+)- and (R)-(-)-octoclothepin have been employed to identify biologically active conformations of these compounds with respect to dopamine receptor antagonism and amine-uptake inhibition. In contrast to what is commonly assumed, these studies indicate that the conformation of (S)-(+)-octoclothepin responsible for the dopamine receptor antagonism is different from the one observed in the crystal. From least-squares molecular superimpositions with the potent and stereoselective dopamine receptor antagonist (1R,3S)-tefludazine, biologically active conformations for the two compounds on the dopamine receptor have been deduced. This analysis also rationalizes the enantioselectivity of octoclothepin on the dopamine receptor. The X-ray structure of (S)-(+)-octoclothepin is shown to correspond structurally to the 1S,3R enantiomer of tefludazine, which is an amine-uptake inhibitor. This correspondence provides a structural basis for the norepinephrine (NE) uptake blocking properties of octoclothepin. It is predicted that the enantioselectivity of the NE-uptake inhibition of octoclothepin should be low with the S-(+) enantiomer as the more active optical isomer. A comparison of the deduced biologically active conformation of (S)-(+)-octoclothepin with (+)-dexclamol is also discussed on the basis of earlier derived superimposition studies with (+)-dexclamol.

Topics: Antipsychotic Agents; Dibenzocycloheptenes; Dibenzothiepins; Dopamine; Molecular Conformation; Neurotransmitter Uptake Inhibitors; Norepinephrine; Piperazines; Receptors, Dopamine; Stereoisomerism; Structure-Activity Relationship