Synthesis and opioid activity of enantiomeric N-substituted 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolines.
A series of enantiomeric N-substituted 2,3,4,4a,5,6,7,7a-octahydro-1H-benzofuro[3,2-e]isoquinolines was synthesized. The (-)-enantiomers had much greater kappa-, mu-, and delta-opioid receptor binding affinity than the corresponding (+)-enantiomers. Compounds (-)-1a, (-)-1b, and (-)-1c displayed subnanomolar binding affinity for the mu-receptor, and (-)-1b had a high affinity for the kappa-receptor. Compound (-)-1a was a mu-partial agonist and kappa-antagonist. Compound (-)-1b was a potent neutral mu-antagonist (K(d) = 0.22 nM) and a kappa-partial agonist.
Hsin
Ling-Wei
LW
School of Pharmacy, College of Medicine, National Taiwan University, Number 1, Jen-Ai Road, Taipei, Taiwan 10018, ROC. lwhsin@ntu.edu.tw
Chang
Li-Te
LT
Rothman
Richard B
RB
Dersch
Christina M
CM
Fishback
James A
JA
Matsumoto
Rae R
RR
D000701:Analgesics, Opioid / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001921:Brain / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051381:Rats; D011957:Receptors, Opioid / Q000737:chemistry / Q000378:metabolism*; D017473:Receptors, Opioid, kappa / Q000737:chemistry / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000737:chemistry / Q000378:metabolism*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D007546:Isoquinolines; D011957:Receptors, Opioid; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate)