STUDIES OF THE ACTIVE CONFORMATION OF A NOVEL SERIES OF BENZAMIDE DOPAMINE D2 AGONISTS

Analogs of dopamine D2 agonist 11 were prepared in which a rigid trans decalin ring system was used to mimic various conformations of 11. Th e four rigid analogs where compared for their ability to bind to the D A D2 receptor and to inhibit forskolin-stimulated cAMP formation, a me asure of DA agonist activity. Of the four rigid analogs of compound 11 , only compound 12b had significant activity in both assays. Molecular modeling studies of 12a-d showed each had a single conformation with regard to the distance between the benzamide aryl-centroid and the 4-n itrogen atom of the pyridylpiperazine. Compound 12b was shown to have a greater distance between these functionalities (11.8 Angstrom) as co mpared to the other isomers (9.8-10.4 Angstrom). The distance between these two functionalities in 12b was similar to that of a conformer of 11 which has an extended conformation. This suggest that 11 is likely in an extended conformation when bound to the DA D2 receptor.