Substituted tetrahydroisoquinolines as selective antagonists for the orexin 1 receptor.
Increasing evidence implicates the orexin 1 (OX1) receptor in reward processes, suggesting OX1 antagonism could be therapeutic in drug addiction. In a program to develop an OX1 selective antagonist, we designed and synthesized a series of substituted tetrahydroisoquinolines and determined their potency in OX1 and OX2 calcium mobilization assays. Structure-activity relationship (SAR) studies revealed limited steric tolerance and a preference for electron deficiency at the 7-position. Pyridylmethyl groups were shown to be optimal for activity at the acetamide position. Computational studies resulted in a pharmacophore model and confirmed the SAR results. Compound 72 significantly attenuated the development of place preference for cocaine in rats.
Research Triangle Institute , Research Triangle Park, North Carolina 27709, United States.
David A
DA
Perrey
Nadezhda A
NA
German
Brian P
BP
Gilmour
Jun-Xu
JX
Li
Danni L
DL
Harris
Brian F
BF
Thomas
Yanan
Y
Zhang
D000818:Animals; D003042:Cocaine / Q000494:pharmacology; D064446:Orexin Receptors; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D018013:Receptors, Neuropeptide / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000494:pharmacology*
D064446:Orexin Receptors; D043562:Receptors, G-Protein-Coupled; D018013:Receptors, Neuropeptide; D044005:Tetrahydroisoquinolines; D003042:Cocaine