Enantioselective Syntheses of Dopaminergic (R)- and (S)-Benzyltetrahydroisoquinolines

• Published in: Journal of medicinal chemistry 2001-05, Vol.44 (11), p.1794-1801
• Main Authors: Cabedo, Nuria, Andreu, Inmaculada, Ramírez de Arellano, M. Carmen, Chagraoui, Abdeslam, Serrano, Angel, Bermejo, Almudena, Protais, Philippe, Cortes, Diego
• Format: Article
• Language: English
• Subjects: Animals; Benzazepines - metabolism; Benzyl Compounds - chemical synthesis; Benzyl Compounds - chemistry; Benzyl Compounds - metabolism; Binding, Competitive; Biological and medical sciences; Catecholaminergic system; Corpus Striatum - metabolism; Corpus Striatum - ultrastructure; Crystallography, X-Ray; Dopamine - metabolism; Dopamine Antagonists - chemical synthesis; Dopamine Antagonists - chemistry; Dopamine Antagonists - metabolism; In Vitro Techniques; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - metabolism; Ligands; Male; Medical sciences; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Raclopride - metabolism; Radioligand Assay; Rats; Rats, Wistar; Receptors, Dopamine D1 - metabolism; Receptors, Dopamine D2 - metabolism; Stereoisomerism; Structure-Activity Relationship; Synaptosomes - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm001128u

Optically pure (1S,R)- and (1R,S)-benzyltetrahydroisoquinolines (BTHIQs), 12a,b as the major diastereomers, were prepared by stereoselective reduction of the isoquinolinium salt possessing (R)- and (S)-phenylglycinol as the chiral auxiliary, respectively. The absolute configurations of (1S,R)-13a hydrochloride (O-debenzoylated derivative from 12a) and (1R,S)-12b diastereomers were unambiguously determined by single-crystal X-ray analysis. Reductive removal of the chiral auxiliary group, subsequent N-propylation, and cleavage of the methylenedioxy group furnished the optically active catecholamines (1S)-16a and (1R)-16b in good overall yield. We have separately prepared for the first time pairs of dopaminergic 1-BTHIQs enantiomers through a classical methodology in asymmetric synthesis. The (1S)-enantiomers (14a−16a) bind to D1 and D2 dopamine receptors with affinities 5−15 times higher than those of the corresponding (1R)-enantiomers (14b−16b). Moreover, (1S)-14a inhibits [3H]dopamine uptake with high affinity. It appears that synthesis and testing of (S)-enantiomers of BTHIQ are very important for the search for new active drugs at dopamine receptors.