Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor

N E Austin; K Y Avenell; I Boyfield; C L Branch; M S Hadley; P Jeffrey; C N Johnson; G J Macdonald; D J Nash; G J Riley; A B Smith; G Stemp; K M Thewlis; A K Vong; M D Wood

doi:10.1016/s0960-894x(01)00037-3

Design and synthesis of novel 2,3-dihydro-1H-isoindoles with high affinity and selectivity for the dopamine D3 receptor

Bioorg Med Chem Lett. 2001 Mar 12;11(5):685-8. doi: 10.1016/s0960-894x(01)00037-3.

Authors

N E Austin¹, K Y Avenell, I Boyfield, C L Branch, M S Hadley, P Jeffrey, C N Johnson, G J Macdonald, D J Nash, G J Riley, A B Smith, G Stemp, K M Thewlis, A K Vong, M D Wood

Affiliation

¹ SmithKline Beecham Pharmaceuticals, New Frontiers Science Park, Harlow, Essex, UK.

PMID: 11266169
DOI: 10.1016/s0960-894x(01)00037-3

Abstract

Starting from the tetrahydroisoquinoline SB-277011 1, a novel series of 5-substituted-2,3-dihydro-1H-isoindoles has been designed. Subsequent optimisation resulted in identification of 19, which has high affinity for the dopamine D3 receptor (pKi 8.3) and > or = 100-fold selectivity over other aminergic receptors. In rat studies 19 was brain penetrant with an excellent pharmacokinetic profile (oral bioavailability 77%, t1/2 5.2h).

MeSH terms

Animals
Brain / metabolism
CHO Cells
Cricetinae
Dopamine Antagonists / chemical synthesis
Dopamine Antagonists / chemistry*
Dopamine Antagonists / metabolism
Dopamine Antagonists / pharmacology*
Drug Design
Humans
Indoles / chemical synthesis
Indoles / chemistry*
Indoles / metabolism
Indoles / pharmacology*
Models, Molecular
Molecular Structure
Radioligand Assay
Rats
Receptors, Dopamine D2 / metabolism*
Receptors, Dopamine D3

Substances

DRD3 protein, human
Dopamine Antagonists
Drd3 protein, rat
Indoles
Receptors, Dopamine D2
Receptors, Dopamine D3