Synthesis and Biological Evaluation of 14-Alkoxymorphinans. Part 9. 14-O-ethyl-5-methylnaltrexone, and opioid antagonist with unusual selectivity

✍ Scribed by Helmut Schmidhammer; Andrea Schratz; Charlotte Schmidt; Dinesh Patel; John R. Traynor

• Publisher: John Wiley and Sons
• Year: 1993
• Tongue: German
• Weight: 325 KB
• Volume: 76
• Category: Article
• ISSN: 0018-019X
• DOI: 10.1002/hlca.19930760131

✦ Synopsis

Ethyl-5-methylnaloxone (7) and 14-0-ethyl-5-methylnaltrexone (8) have been prepared starting from 14-0-ethyl-5-methyloxycodone (9) in several steps. Both, 7 and 8, were found to be opioid antagonists in vitro and in vivo. Compound 7 exhibited some selectivity forp opioid receptors, whereas compound 8 did not show selectivity for any of the receptor types. In the AcOH-writhing antagonism test, 8 was not able to antagonize morphineinduced antinociception, but antagonized fentanyl-and sufentanil-induced antinociception.

Introduction. -The introduction of a 14-0-alkyl group (MeO, EtO) into naloxone (1) and naltrexone (2), respectively, did not significantly alter the in vitro and in vivo potencies of these two opioid antagonists [2], while introduction of a 5-Me group reduced the antagonist properties and enhanced the agonist effects producing partial agonists [3]. In the N-methylmorphinan-6-one series of opioid agonists, a 5-Me group slightly decreased