Nitrogen-bridged conformationally constrained etorphine analogues. Synthesis and biological evaluation.
Three N-C8-bridged analogues 4-6 of the opiate etorphine (3) were synthesized and evaluated for opiate agonism and antagonism. In each case ring closure was effected by intramolecular N-alkylation with a suitably developed C8 side chain. Another key synthetic step was the selective monoprotection of diol 11, which allowed independent elaborations of the C7 and C8 side chains. All three analogues showed distinctly diminished agonist activities when compared to the corresponding N-methyl compound, 19(R)-n-butylorvinol (3). Furthermore, no antagonist activity was detectable. The results demonstrate that the conformation at the amino nitrogen in rigid morphinans is critical for potent opiate activity.
Maurer
P J
PJ
Department of Chemistry, University of California, Berkeley 94720.
Rapoport
H
H
D000698:Analgesia; D000818:Animals; D005048:Etorphine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D008297:Male; D008968:Molecular Conformation; D009019:Morphinans / Q000138:chemical synthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D009019:Morphinans; D005048:Etorphine