Benzamides derived from 1,2-diaminocyclopropane as novel ligands for human D2 and D3 dopamine receptors.

Benzamides (3a-f) derived from 4-amino-5-chloro-2-methoxybenzoic acid and either cis or trans 1,2-diaminocyclopropane were synthesised and were evaluated in binding assays employing, bovine striatal D2 receptors, recombinant human hD2 and hD3 receptors expressed in CHO cells and rat, cortical 5-HT3 and striatal 5-HT4 receptors. The cis and trans isomers of the derivatives were isolated and characterised. The results demonstrated the superiority of the cis conformers over the trans conformers in dopamine receptor binding assays (Ki hD2 = 13.4 and 6.9 nM and Ki hD3 = 17.7 and 4.5 nM for the cis-3b and cis-3f compounds, respectively; Ki hD2 = 816 and >l000 nM and Ki hD3 = 469 and >1000 nM for the corresponding trans-3b and trans-3f compounds respectively). The cis compounds are folded: the benzamide group and the basic nitrogen atom were in a syn relationship. Compound 3f can be superimposed with a conformation of the tropane derivative, BRL 25594, having the benzyl group in an axial position to give a suitable fit, indicating that both compounds may have a common binding site in the dopamine receptor.