4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors

K W Moore; K Bonner; E A Jones; F Emms; P D Leeson; R Marwood; S Patel; S Patel; M Rowley; S Thomas; R W Carling

doi:10.1016/s0960-894x(99)00169-9

4-N-linked-heterocyclic piperidine derivatives with high affinity and selectivity for human dopamine D4 receptors

Bioorg Med Chem Lett. 1999 May 3;9(9):1285-90. doi: 10.1016/s0960-894x(99)00169-9.

Authors

K W Moore¹, K Bonner, E A Jones, F Emms, P D Leeson, R Marwood, S Patel, S Patel, M Rowley, S Thomas, R W Carling

Affiliation

¹ Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, Essex, UK. [email protected]

PMID: 10340615
DOI: 10.1016/s0960-894x(99)00169-9

Abstract

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.

MeSH terms

Animals
CHO Cells
Clozapine / analogs & derivatives
Clozapine / chemical synthesis
Clozapine / pharmacology
Cricetinae
Humans
Kinetics
Piperidines / chemical synthesis*
Piperidines / pharmacology
Receptors, Dopamine D2 / metabolism*
Receptors, Dopamine D4
Serotonin Antagonists / chemical synthesis
Serotonin Antagonists / pharmacology

Substances

DRD4 protein, human
Piperidines
Receptors, Dopamine D2
Serotonin Antagonists
Receptors, Dopamine D4
piperidine
Clozapine