Investigation on central dopaminergic receptors (D-2) using the antagonistic properties of new benzamides

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Abstract
The topography of the central dopaminergic receptor (D−2) has been studied using some analogues of tropapride, a new benzamide derivative, and sulpiride and clebopride as reference drugs. The compounds were compared by testing their ability to compete with [3H]spiperone in an in-vitro binding test and by measuring their potency as antagonists of apomorphine-induced climbing in mice. Tropapride was the most active compound, both in-vitro and in-vivo. With the amide group substituted in the 2−position of the tropane ring, the antidopaminergic activity of the compounds was much less than that of the 3−substituted derivatives. The interaction of the tropane derivatives with the D−2 receptor site is stereoselective as the equatorial stereoisomer was much more active than the axial isomer. The ethylene bridge present in the tropane derivatives but not in the corresponding piperidinyl analogues increases the affinity of the tropane derivatives for the D−2 receptor. Interaction with the D−2 receptor was confirmed as being Na+-dependent. The presence of a benzyl substituent on the basic nitrogen atom seems to be essential in the tropane series emphasizing the important role played in this series by the lipophilic auxiliary binding site postulated in Olson. In conclusion, the tropane skeleton may be considered a useful pharmacophoric group in the design of new dopaminergic drugs.