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10-Ketomorphinan and 3-Substituted-3-desoxymorphinan Analogues as Mixed κ and μ Opioid Ligands: Synthesis and Biological Evaluation of Their Binding Affinity at Opioid Receptors

Ao Zhang,^† Wennan Xiong,^† Jean M. Bidlack,^‡ James E. Hilbert,^‡ Brian I. Knapp,^‡ Mark P. Wentland,^§ and John L. Neumeyer*^†

Alcohol and Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478, Department of Pharmacology and Physiology, School of Medicine and Dentistry, University of Rochester, Rochester, New York 14642, and Department of Chemistry, Rensselaer Polytechnic Institute, Troy, New York 12180

J. Med. Chem., 2004, 47 (1), pp 165–174

DOI: 10.1021/jm0304156

Publication Date (Web): December 9, 2003

†

Harvard Medical School.

‡

University of Rochester.

Rensselaer Polytechnic Institute.

To whom correspondence should be addressed. Tel: 617-855-3388; Fax: 617-855-2519; E-mail: Neumeyer@mclean.harvard.edu.

Abstract

A series of 10-ketomorphinan analogues were synthesized, and their binding affinity at all three opioid receptors was investigated. In most cases, high affinity at μ and κ receptors, and lower affinity at δ receptor was observed, resulting in good selectivity for μ and κ receptors. A wide range of substituents can be accommodated on the nitrogen position. The N-(S)-tetrahydrofurfuryl analogue 11 displayed the highest affinity at all three receptors. The N-cyclobutylmethyl analogue 13 gave both high affinity and selectivity at κ receptor, and N-2-phenylethyl analogue 18 exhibited good affinity and selectivity at μ receptor. Further modifications of the 3-substituent indicated that one H-bond donor was an essential requirement for good affinity at μ and κ receptors. Similar modifications were investigated at the 3-OH group of morphinans: levorphanol (2a), cyclorphan (2b), and MCL-101 (2c) lacking the 10-keto group. The 3-amino bioisosteric analogues (40 and 41) displayed reasonably good affinity at μ and κ receptors. The 3-carboxamido replacement (compounds 46−48) in the morphinan subseries resulted in similar affinities comparable to their corresponding 3-OH congeners. The high affinity of these carboxamido analogues, along with their greater lipophilicity and metabolic stability, make them promising candidates for further pharmacological investigation.