Author/Authors :
Ian Collins، نويسنده , , Michael Rowley، نويسنده , , William B Davey، نويسنده , , Frances Emms، نويسنده , , Rosemarie Marwood، نويسنده , , Shil Patel، نويسنده , , Smita Patel، نويسنده , , Alan Fletcher، نويسنده , , Ian C Ragan، نويسنده , , Paul D Leeson، نويسنده , , Ann L. Scott، نويسنده , , Theodore Broten، نويسنده ,
Abstract :
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.
