4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors.
The syntheses of a number of different N-linked heterocyclic pyrazole replacements based on the structure 1 are described (compounds 3-12) as hD4 ligands. After further optimisation the best compound identified was 13 which has high affinity for hD4 (5.2 nM) and >300-fold selectivity for hD4 receptors over hD2 and hD3 receptors.
Moore
K W
KW
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK. Kevin_Moore@Merck.com
Bonner
K
K
Jones
E A
EA
Emms
F
F
Leeson
P D
PD
Marwood
R
R
Patel
S
S
Patel
S
S
Rowley
M
M
Thomas
S
S
Carling
R W
RW
D000818:Animals; D016466:CHO Cells; D003024:Clozapine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology; D006224:Cricetinae; D006801:Humans; D007700:Kinetics; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D050638:Receptors, Dopamine D4; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000494:pharmacology
C493599:DRD4 protein, human; D010880:Piperidines; D017448:Receptors, Dopamine D2; D012702:Serotonin Antagonists; D050638:Receptors, Dopamine D4; C032727:piperidine; D003024:Clozapine