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

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 mu and kappa receptors, and lower affinity at 6 receptor was observed, resulting in good selectivity for mu and kappa 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 kappa receptor, and N-2-phenylethyl analogue 18 exhibited good affinity and selectivity at mu receptor. Further modifications of the 3-substituent indicated that one H-bond donor was an essential requirement for good affinity at mu and kappa 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 mu and kappa 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.