Probes for narcotic receptor mediated phenomena. 37. Synthesis and opioid binding affinity of the final pair of oxide-bridged phenylmorphans, the ortho- and para-b-isomers and their N-phenethyl analogues, and the synthesis of the N-phenethyl analogues of the ortho- and para-d-isomers.
In the isomeric series of 12 racemic topologically rigid N-methyl analogues of oxide-bridged phenylmorphans, all but two of the racemates, the ortho- and para-b-oxide-bridged phenylmorphans 20 and 12, have remained to be synthesized. The b-isomers were very difficult to synthesize because of the highly strained 5,6-trans-fused ring junction that had to be formed. Our successful strategy required functionalization of the position para (or ortho) to a fluorine atom on the aromatic ring using an electron-withdrawing nitro group to activate that fluorine. The racemic N-phenethyl analogues 24 and 16 were moderately potent kappa-receptor antagonists in the [(35)S]GTPgammaS assay. We synthesized the N-phenethyl-substituted oxide-bridged phenylmorphans in the ortho- and para-d-oxide-bridged phenylmorphan series (51 and 52) which had not been previously evaluated using contemporary receptor binding assays to see whether they also have higher affinity for opioid receptors than their N-methyl relatives 46 and 47.
Kurimura
Muneaki
M
Drug Design and Synthesis Section, Chemical Biology Research Branch, National Institute on Drug Abuse, National Institutes of Health, Department of Health and Human Services, 5625 Fishers Lane, Room 4N03, Bethesda, Maryland 20892-9415, USA.
Liu
Hehua
H
Sulima
Agnieszka
A
Hashimoto
Akihiro
A
Przybyl
Anna K
AK
Ohshima
Etsuo
E
Kodato
Shinichi
S
Deschamps
Jeffrey R
JR
Dersch
Christina M
CM
Rothman
Richard B
RB
Lee
Yong Sok
YS
Jacobson
Arthur E
AE
Rice
Kenner C
KC
D000701:Analgesics, Opioid / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D004583:Electrons; D005461:Fluorine / Q000737:chemistry; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008956:Models, Chemical; D008958:Models, Molecular; D009584:Nitrogen / Q000737:chemistry; D010087:Oxides / Q000737:chemistry*; D011485:Protein Binding; D011957:Receptors, Opioid / Q000737:chemistry
D000701:Analgesics, Opioid; D008024:Ligands; D010087:Oxides; D011957:Receptors, Opioid; D005461:Fluorine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009584:Nitrogen