Stereochemical studies on medicinal agents. 23. Synthesis and biological evaluation of 6-amino derivatives of naloxone and naltrexone

Abstract

Epimeric 6-amino derivatives of naloxone and naltrexone have been synthesized and the configuration at the C-6 chiral center was determined from NMR studies. All of the derivatives possess narcotic antagonist activity in mice, with each of the 6beta epimers having greater potency than the corresponding 6alpha epimers. In vitro binding experiments indicate that the affinities of these epimers parallel thier in vivo potencies. Slight antinociceptic properties were observed with three of the four compounds. The naloxone derivatives 3a and 3b appear to be attractive candidates for investigation as long-acting narcotic antagonists in view of their fourfold greater duration of action relative to the other antagonists (1, 2, 4a, and 4b).

Synthesis and Pharmacological Activities of 6-Glycine Substituted 14-Phenylpropoxymorphinans, a Novel Class of Opioids with High Opioid Receptor Affinities and Antinociceptive Potencies

“…J (5,6) values for 6α-amino epimers are smaller (3.2−4.0 Hz) than for 6β-amino epimers (6.5−7.8 Hz). 29,34,35 The results for compounds 11 − 18 agree with the earlier findings.…”

Synthesis of 6‐Amino Acid Substituted Derivatives of the Highly Potent Analgesic 14‐O‐Methyloxymorphone

“…Configurational assignments at C(6) were based on the coupling constants (J(5,6)) between HÀC(5) and HÀC (6). J(5,6) Values for 6a-amino epimers are smaller (3.2 ± 4.0 Hz) than for 6b-amino compounds (6.5 ± 7.8 Hz) [31] [32]. The results for the title compounds agree with those findings: their J(5,6) values range from 2.8 to 3.8 Hz for 6a-amino derivatives and from 7.0 to 7.6 Hz for 6b-amino derivatives.…”

Reduction of conditioned pain modulation in humans by naltrexone: an exploratory study of the effects of pain catastrophizing

“…Naltrexone has greater potency and duration of action compared to naloxone (Zimmerman & Leander, 1990). Based on antagonistic evaluations of opioid analgesia in rodent preparations, naltrexone was more potent than naloxone (Jiang et al, 1977; Pert et al, 1973; Takemori & Portoghese, 1984; Zimmerman & Leander, 1990) including its active metabolite (Porter et al, 2002). For naloxone, plasma concentrations are dependent on the route of administration (∼10 min for intravenous) while concentrations peak around 45–60 min for orally administered naltrexone.…”