Dopamine D3 receptor selective ligands with varying intrinsic efficacies at adenylyl cyclase inhibition and mitogenic signaling pathways

A panel of structurally related substituted 4-phenylpiperazines with nanomolar affinity and selectivity at D3 dopamine receptors has been synthesized. Compounds in which a heterocyclic (2-phenyl pyridyl, 3-phenyl pyridyl, benzothiophene, or benzofuran) moiety is adjacent to the amide was varied and/or a double bond (trans-butenyl) replaced the four-carbon aliphatic chain linking the arylamide with the 4-phenylpiperazine moiety were compared for (a) affinity at human D2 and D3 dopamine receptors, (b) intrinsic efficacy using an adenylyl cyclase inhibition assay, and (c) intrinsic efficacy using a mitogenic assay. All 16 compounds were (a) more efficacious for the D3 receptor cyclase inhibition assay than for the D3 receptor mitogenic assay and (b) exhibited the same or greater efficacy at D3 compared to D2 receptor (with the exception of one compound). Although the heterocyclic amide moiety appears to be the pivotal structural element determining the intrinsic efficacy of our D3 receptor selective compounds, the magnitude of the efficacy is modulated by the (a) substituent(s) on the phenyl piperazine and (b) the saturation of the four-carbon chain that links the arylamide and the phenylpiperazine. In addition, our ligands are functionally selective, because they can have differing intrinsic efficacies for the cyclase inhibition and the mitogenic activation signaling pathways. Compounds that are essentially full agonists at the cyclase assay appear to be only partial agonists in the mitogenic assay and compounds that are partial agonists in our cyclase assay are partial agonists or antagonists in the mitogenic assay.