3-(1-Piperazinyl)-4,5-dihydro-1H-benzo[g]indazoles: High affinity ligands for the human dopamine D4 receptor with improved selectivity over ion channels

Article abstract of DOI:10.1016/S0968-0896(98)00028-5

3-(4-Piperidinyl)-5-arylpyrazoles, such as 1, were selective for the cloned human dopamine D₄ receptor (hD₄), but also showed affinity at voltage sensitive calcium, sodium and potassium ion channels. A combination of substituent changes to reduce the basicity of the piperidine nitrogen and conformational restriction to give 4,5-dihydro-1H-benzo[g]indazoles reduced this ion channel affinity at the expense of selectivity for hD₄ over other dopamine receptors. Incorporation of piperazine into the 4,5-dihydro-1H-benzo[g]indazoles in place of piperidine gave a novel series of high affinity, selective, orally bioavailable hD₄ ligands, such as 16, with improved selectivity over ion channels. Copyright (C) 1998 Elsevier Science Ltd.