Investigation of Beckett–Casy model 2: Synthesis of novel 15–16 nornaltrexone derivatives and their pharmacology

Abstract

We synthesized novel 15–16 nornaltrexone derivatives 9, 11 and 22 to examine the importance of the cavity in the Beckett–Casy model, which was proposed to interact with the 15–16 ethylene moiety in the morphine structure. All the synthesized compounds showed lower affinities for the opioid receptor than did the naltrexone (10). The binding affinities of 14-OH derivatives 11, in which the rotation of the 9–17 bond would be restricted by an intramolecular hydrogen bond, was improved compared to the corresponding 14-H derivatives 9. Compound 22 whose 9–17 bond was strictly fixed by the ethylene bridge hardly bound to the opioid receptor. Compound 26 also showed very weak binding affinity in spite of the existence of the 15–16 ethylene unit. We proposed an important role for the orientation of the lone electron pair on the 17-nitrogen rather than the significance of the cavity in the Beckett–Casy model.