Synthesis and delta-opioid receptor antagonist activity of a naltrindole analogue with a regioisomeric indole moiety.
Indolomorphinans 2 and 3, in which the indole moiety is fused to the 7,8-position of the morphinan system, have been synthesized from dihydropseudocodeinone 4 and evaluated for antagonist activity on the mouse vas deferens (MVD) and guinea pig ileum (GPI) preparations. Indolomorphinan 2 was found to be approximately 1/60th as potent as naltrindole 1 in the MVD and an agonist in the GPI preparation. A comparable difference in affinity between 1 and 2 was observed. The methyl analogue 3 was inactive in both preparations. The results of this study support the idea that the regio orientation of the indolic benzene moiety of 1 is optimal for delta-opioid receptor antagonist activity. It is proposed that the proper alignment of the benzene moiety with an address subsite on the delta receptor is critical for potent delta antagonist activity.
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
P S
PS
Portoghese
S
S
Ohkawa
S T
ST
Moe
A E
AE
Takemori
D000818:Animals; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007536:Isomerism; D051379:Mice; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*
D007211:Indoles; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D009271:Naltrexone; C055382:naltrindole