Synthesis, Binding Affinity, and Functional in Vitro Activity of 3-Benzylaminomorphinan and 3-Benzylaminomorphine Ligands at Opioid Receptors

• Published in: Journal of medicinal chemistry Vol. 55; no. 8; pp. 3878 - 3890
• Main Authors: Neumeyer, John L, Zhang, Bin, Zhang, Tangzhi, Sromek, Anna W, Knapp, Brian I, Cohen, Dana J, Bidlack, Jean M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.04.2012; Amer Chemical Soc
• Subjects: Animals; Benzylamines - chemical synthesis; Benzylamines - metabolism; Binding, Competitive; Chemistry, Medicinal; CHO Cells; Cricetinae; Guanosine 5'-O-(3-Thiotriphosphate) - metabolism; Humans; Kinetics; Life Sciences & Biomedicine; Morphinans - chemical synthesis; Morphinans - metabolism; Pharmacology & Pharmacy; Receptors, Opioid - drug effects; Receptors, Opioid - metabolism; Receptors, Opioid, delta - metabolism; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - metabolism; Science & Technology; Structure-Activity Relationship; MU; INTRAVENOUS MORPHINE; KAPPA; ANALOGS; SUFENTANIL
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm3001086

A series of 3-benzylamino-3-desoxymorphinan (I) and 3-benzylamino-3-desoxymorphine (II) derivatives were synthesized and evaluated for their binding affinities, and functional activity data are presented at MOR, KOR, and DOR. Some of these ligands were found to have high binding affinity at MOR and KOR and displayed increased selectivity at MOR over KOR and DOR compared to butorphan or cyclorphan. The most selective compound, 3-(3′-hydroxybenzyl)amino-17-methylmorphinan (4g) (24-fold MOR to KOR and 1700-fold MOR to DOR) also showed high binding affinity (0.42 nM to MOR) and was a full agonist in the [35S]GTPγS binding assay. 2-(3′-Hydroxybenzyl)amino-17-cyclopropylmethylmorphinan (17) was found to be a KOR-selective ligand (150-fold over MOR and >10000-fold over the DORs). Most 3-benzylaminomorphinan derivatives were partial agonists at MOR and full agonists at KOR in the [35S]GTPγS binding assay.