Investigation of Beckett-Casy model 2: synthesis of novel 15-16 nornaltrexone derivatives and their pharmacology.
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.
Nagase
Hiroshi
H
School of Pharmacy, Kitasato University, Tokyo, Japan. nagaseh@pharm.kitasato-u.ac.jp
Imaide
Satomi
S
Tomatsu
Miyuki
M
Nemoto
Toru
T
Nakajima
Mayumi
M
Nakao
Kaoru
K
Mochizuki
Hidenori
H
Fujii
Hideaki
H
D004583:Electrons; D005030:Ethylenes; D006860:Hydrogen Bonding; D009020:Morphine / Q000737:chemistry; D009271:Naltrexone / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D009292:Narcotic Antagonists; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship
D005030:Ethylenes; D009292:Narcotic Antagonists; D011957:Receptors, Opioid; D009271:Naltrexone; D009020:Morphine; C036216:ethylene