Potent and selective indolomorphinan antagonists of the kappa-opioid receptor.
The indole moiety in the delta-opioid antagonist, naltrindole (2, NTI), was employed as a scaffold to hold an "address" for interaction with the kappa-opioid receptor. The attachment of the address to the 5'-position of the indole moiety was based on superposition of NTI upon the kappa antagonist, norbinaltorphimine (1, norBNI). A variety of cationic groups were employed as a kappa address in an effort to investigate its interaction with the anionic address subsite, Glu297, on the kappa receptor. Some of the groups that were employed for this purpose were amines, amidines, guanidines, and quaternary ammonium. Members of the series were found to have a varying degree of kappa antagonist potency and kappa selectivity when tested in smooth muscle preparations. The 5'-guanidine derivative 12a (GNTI) was the most potent member of the series and had the highest kappa selectivity ratio. GNTI was 2 times more potent and 6-10-fold more selective than norBNI (1). In general, the order of potency in the series was: guanidines > amidines approximately quaternary ammonium > amines. The kappa antagonist potency appeared to be a function of a combination of the pK(a) and distance constraint of the cationic substituent of the ligand. Receptor binding studies were qualitatively in agreement with the pharmacological data. Molecular modeling studies on 12a suggested that the protonated N-17 and guanidinium groups of GNTI are associated with Asp138 (TM3) and Glu297 (TM6), respectively, while the phenolic hydroxyl may be involved in donor-acceptor interactions with the imidazole ring of His291. It was concluded that the basis for the high kappa selectivity of GNTI is related both to association with the nonconserved Glu297 residue and to unfavorable interactions with an equivalent position in mu- and delta-opioid receptors.
Stevens
W C
WC
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis, Minnesota 55455, USA.
Jones
R M
RM
Subramanian
G
G
Metzger
T G
TG
Ferguson
D M
DM
Portoghese
P S
PS
D002460:Cell Line; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000737:chemistry*; D008958:Models, Molecular; D009019:Morphinans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D009022:Morphine Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry; D009292:Narcotic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
C411465:17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5'-guanidinyl-3,14-dihydroxyindolo(2',3'-6,7)morphinan; D006146:Guanidines; D007211:Indoles; D009019:Morphinans; D009022:Morphine Derivatives; D009292:Narcotic Antagonists; D017473:Receptors, Opioid, kappa; D009271:Naltrexone; C055382:naltrindole