A series of 3-benzylamino-3-desoxymorphinan I  and 3-benzylamino-3-desoxymorphine II  derivatives were synthesized and evaluated for their binding affinities at MOR, KOR, and DOR. Some of these ligands were found to have high affinity at MOR and KOR and displayed greater selectivity for the MOR over KOR and DOR compared to cyclorphan III  or  butorphan IV  . Activities for high affinity analogs (Ki = 1 nM) were evaluated using the [35S]GTP?S functional assay. The most mu-selective compound, 3-(3'-hydroxybenzyl)amino-17-methylmorphinan (MCL-725) (24-fold MOR to KOR and 1700-fold MOR to DOR) also had high affinity (Ki = 0.42 nM to the MOR). Although morphine analogs IV  only had moderate affinities at the MOR, MCL-720, MCL-717, and MCL-721 (Ki = 8.5, 7.0, and 13 nM, respectively) had good selectivity for the MOR. The structure activity relationships of the 3-benzylamino-3-desoxymorphinans I  and 3-benzylamino-3-desoxymorphines II  will be presented.

Synthesis and evaluation of 3-benzylaminomorphinans at the opioid receptors

243rd National Meeting (2012)

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