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.
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.
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Center, Harlow, Essex, UK. ianvcollins@merck.com
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I
Collins
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M
Rowley
W B
WB
Davey
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Emms
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Marwood
S
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Patel
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S
Patel
A
A
Fletcher
I C
IC
Ragan
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PD
Leeson
A L
AL
Scott
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T
Broten
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D016466:CHO Cells; D015220:Calcium Channels / Q000378:metabolism; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics; D015640:Ion Channel Gating; D007473:Ion Channels / Q000378:metabolism*; D008024:Ligands; D018482:Muscle, Skeletal / Q000378:metabolism; D015221:Potassium Channels / Q000378:metabolism; D011817:Rabbits; D051381:Rats; D017448:Receptors, Dopamine D2 / Q000096:biosynthesis / Q000378:metabolism*; D050638:Receptors, Dopamine D4; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D015222:Sodium Channels / Q000378:metabolism; D013329:Structure-Activity Relationship
C114381:3-(4-(2-(2-chlorophenyl)ethyl)-1-piperazinyl)-4,5-dihydro-1H-benzo(g)indazole; D015220:Calcium Channels; C493599:DRD4 protein, human; C493601:Drd4 protein, rat; D007191:Indazoles; D007473:Ion Channels; D008024:Ligands; D015221:Potassium Channels; D017448:Receptors, Dopamine D2; D011994:Recombinant Proteins; D015222:Sodium Channels; D050638:Receptors, Dopamine D4