N-substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines are opioid receptor pure antagonists.
N-Substituted cis-4a-(3-hydroxyphenyl)-8a-methyloctahydroisoquinolines (6a-g) were designed and synthesized as conformationally constrained analogues of the trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4) class of opioid receptor pure antagonists. The methyloctahydroisoquinolines 6a-g can exist in conformations where the 3-hydroxyphenyl substituent is either axial or equatorial, similar to the (3-hydroxyphenyl)piperidines 4. The 3-hydroxyphenyl equatorial conformation is responsible for the antagonist activity observed in the (3-hydroxyphenyl)piperidine antagonists. Single-crystal X-ray analysis of 6a shows that the 3-hydroxyphenyl equatorial conformation is favored in the solid state. Molecular modeling studies also suggest that the equatorial conformation has lower potential energy relative to that of the axial conformation. Evaluation of 6a-g in the [(35)S]GTP-gamma-S in vitro functional assay showed that they were opioid receptor pure antagonists. N-[4a-(3-Hydroxyphenyl)-8a-methyl-2-(3-phenylpropyl)octahydroisoquinoline-6-yl]-3-(piperidin-1-yl)propionamide (6d) with a K(e) of 0.27 nM at the kappa opioid receptor with 154- and 46-fold selectivity relative to those of the micro and delta receptors, respectively, possessed the best combination of kappa potency and selectivity.
Carroll
F Ivy
FI
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA. fic@rti.org
Chaudhari
Sachin
S
Thomas
James B
JB
Mascarella
S Wayne
SW
Gigstad
Kenneth M
KM
Deschamps
Jeffrey
J
Navarro
Hernán A
HA
D000818:Animals; D044482:Benzeneacetamides / Q000494:pharmacology; D016466:CHO Cells; D006224:Cricetinae; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D020881:Enkephalin, D-Penicillamine (2,5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D009292:Narcotic Antagonists; D011759:Pyrrolidines / Q000494:pharmacology; D011957:Receptors, Opioid / Q000378:metabolism; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors
D044482:Benzeneacetamides; D007546:Isoquinolines; D009292:Narcotic Antagonists; D011759:Pyrrolidines; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D020881:Enkephalin, D-Penicillamine (2,5)-; C045444:U 69593