3-(1-PIPERAZINYL)-4,5-DIHYDRO-1H-BENZO[G]INDAZOLES - HIGH-AFFINITY LIGANDS FOR THE HUMAN DOPAMINE D-4 RECEPTOR WITH IMPROVED SELECTIVITY OVER ION CHANNELS

3-(4-Piperidinyl)-5-arylpyrazole such as 1, were selective for the clo ned human dopamine Dq receptor (hD(4)), but also showed affinity at vo ltage sensitive calcium, sodium and potassium ion channels. A combinat ion of substituent changes to reduce the basicity of the piperidine ni trogen and conformational restriction to give 4,5-dihydro-1H-benzo[g]i ndazoles reduced this ion channel affinity at the expense of selectivi ty 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 hD(4) ligands, such as 16, with improved selectivity over ion channels. (C) 1998 Elsevier Science Ltd. All rights reserved.