Synthesis, opioid receptor binding, and functional activity of 5'-substituted 17-cyclopropylmethylpyrido[2',3':6,7]morphinans.
A series of naltrexone-derived pyridomorphinans possessing various substituents at the 5'-position on the pyridine ring were synthesized and evaluated for opioid receptor binding in rodent brain membranes and functional activity in smooth muscle preparations. While the introduction of aromatic 1-pyrrolyl group (6h) improved the delta affinity and delta antagonist potency of the parent compound (3), the introduction of guanidine group (6i) transformed it to a kappa selective ligand in opioid receptor binding and [35S]GTP-gamma-S functional assays.
Ananthan
Subramaniam
S
Organic Chemistry Department, Southern Research Institute, Birmingham, AL 35255, USA. ananthan@sri.org
Kezar
Hollis S
HS
Saini
Surendra K
SK
Khare
Naveen K
NK
Davis
Peg
P
Dersch
Christina M
CM
Porreca
Frank
F
Rothman
Richard B
RB
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D006146:Guanidines / Q000138:chemical synthesis / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007202:Indicators and Reagents; D008297:Male; D009019:Morphinans / Q000138:chemical synthesis* / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D011957:Receptors, Opioid / Q000187:drug effects / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects
D006146:Guanidines; D007202:Indicators and Reagents; D009019:Morphinans; D009292:Narcotic Antagonists; D011725:Pyridines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009271:Naltrexone