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Development of Novel 1,2,3,4‐Tetrahydroisoquinoline Derivatives and Closely Related Compounds as Potent and Selective Dopamine D 3 Receptor Ligands

2004; Wiley; Volume: 5; Issue: 4 Linguagem: Inglês

10.1002/cbic.200300784

1439-7633

U Mach, Anneke E. Hackling, Sylvie Perachon, Sandrine Ferry, Camille G. Wermuth, Jean‐Charles Schwartz, Pierre Sokoloff, Holger Stark,

Neuropeptides and Animal Physiology

Abstract Based on N ‐alkylated 1,2,3,4‐tetrahydroisoquinoline derivatives, which are structurally related to the partial agonist BP 897, a series of novel, selective dopamine D 3 receptor antagonists has been synthesised. Derivatisation included changes in the arylamide moiety and the tetrahydroisoquinoline substructure leading to compounds with markedly improved selectivities and affinities in the low nanomolar concentration range. From the 55 structures presented here, ( E )‐3‐(4‐iodophenyl)‐ N ‐(4‐(1,2,3,4‐tetrahydroisoquinolin‐2‐yl)butyl)acrylamide ( 51 ) has high affinity ( K i (hD 3 )=12 n M ) and a 123‐fold preference for the D 3 receptor relative to the D 2 receptor subtype. Its pharmacological profile offers the prospect of a novel radioligand as a tool for various dopamine D 3 ‐receptor‐related in vitro and in vivo investigations.