- N-substituted 4β-methyl-5-(3-hydroxyphenyl)-7α-amidomorphans are potent, selective κ opioid receptor antagonists
-
In a previous study, we identified (-)-N-[(1R,4S,5S,7R)-5-(3-hydroxyphenyl) -4-methyl-2-(3-phenylpropyl)-2-azabicyclo[3.3.1]non-7-yl]-3-(1-piperidinyl) propanamide (5a, KAA-1) as the first potent and selective κ opioid receptor antagonist from the 5-(3-hydroxyphenyl)morphan class of opioids. In this study we report an improved synthesis of this class of compounds. The new synthetic method was used to prepare analogues 5b-r where the morphan N-substituent and 7α-amido group were varied. Most of the analogues showed sub-nanomolar potency for the κ opioid receptor and were highly selective relative to the μ and δ opioid receptors. (-)-3-(3,4- Dihydroisoquinolin-2(1H)-yl)-N-{(1R,4S,5S,7R)-5-(3-hydroxyphenyl) -4-methyl-2-[2-(2-methylphenyl)ethyl]-2-azabicyclo[3.3.1]non-7-yl}propanamide (5n, MTHQ) is at least as potent and selective as nor-BNI as a κ opioid receptor antagonist in the [35S]GTP-γ-S in vitro functional test.
- Carroll, F. Ivy,Melvin, Matt S.,Nuckols, Michel C.,Mascarella, S. Wayne,Navarro, Hernán A.,Thomas, James B.
-
p. 1781 - 1791
(2007/10/03)
-