Enantioselective syntheses of dopaminergic (R)- and (S)-benzyltetrahydroisoquinolines.
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.
Cabedo
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N
Departamento de Farmacología, Laboratorio de Farmacognosia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
Andreu
I
I
Ramírez De Arellano
M C
MC
Chagraoui
A
A
Serrano
A
A
Bermejo
A
A
Protais
P
P
Cortes
D
D
D000818:Animals; D001552:Benzazepines / Q000378:metabolism; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D001667:Binding, Competitive; D003342:Corpus Striatum / Q000378:metabolism / Q000648:ultrastructure; D018360:Crystallography, X-Ray; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D008024:Ligands; D008297:Male; D020891:Raclopride / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism
D001552:Benzazepines; D001593:Benzyl Compounds; D018492:Dopamine Antagonists; D007546:Isoquinolines; D008024:Ligands; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D020891:Raclopride; D004298:Dopamine