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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
Author(s) -
Mach Ulrich R.,
Hackling Anneke E.,
Perachon Sylvie,
Ferry Sandrine,
Wermuth Camille G.,
Schwartz JeanCharles,
Sokoloff Pierre,
Stark Holger
Publication year - 2004
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.200300784
Subject(s) - tetrahydroisoquinoline , chemistry , radioligand , agonist , stereochemistry , moiety , receptor , in vivo , dopamine , dopamine receptor d2 , biochemistry , biology , microbiology and biotechnology , neuroscience
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.