Design, synthesis, and characterization of 6beta-naltrexol analogs, and their selectivity for in vitro opioid receptor subtypes.
Since the mu opioid receptor (MOR) is known to be involved in the therapeutically relevant pathways leading to the manifestation of pain and addiction, we are currently studying the specific structural characteristics that promote antagonism at the MOR. The opiates 6beta-naltrexol and 6beta-naltrexamide function as neutral antagonists in in vitro and in vivo systems previously exposed to morphine, and are under investigation as improved treatments for narcotic dependence. In this research, we synthesized and characterized carbamate and sulfonate ester derivates of 6beta-naltrexol that do not contain a protic group at C(6), and evaluated these compounds for opioid receptor affinity. In vitro receptor subtype (mu, kappa, and delta opioid receptors) binding data of the carbamate and sulfonate derivatives is reported. All four compounds synthesized exhibited affinity for the MOR better than the standard 6beta-naltrexol HCl. Based on K(i) data, the order of MOR affinity is as follows: 9>13>14>10>6beta-naltrexol HCl. Carbamate 9 and tosylate 13 displayed subnanomolar affinity for the MOR, while 10 was the most mu-selective compound synthesized. In conclusion, our data indicate that the absence of a hydrogen-bond donor on the C(6) oxygen enhances rather than impedes the in vitro affinity of naltrexol derivatives for the MOR. Additionally, data also suggest that increasing the bulk around C(6) may allow control of subtype selectivity within these compound series.
University of New England, Chemistry & Physics Department, Biddeford, ME, United States.
Andrea L
AL
Pelotte
Ryan M
RM
Smith
Mario
M
Ayestas
Christina M
CM
Dersch
Edward J
EJ
Bilsky
Richard B
RB
Rothman
Amy M
AM
Deveau
D000818:Animals; D016466:CHO Cells; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry; D011957:Receptors, Opioid / Q000378:metabolism*; D017465:Receptors, Opioid, delta / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000378:metabolism; D013463:Sulfuric Acid Esters / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014162:Transfection
D002219:Carbamates; D011957:Receptors, Opioid; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D013463:Sulfuric Acid Esters; C010410:6 beta-hydroxynaltrexone; D009271:Naltrexone