Phenylpropyloxyethylamines: Opioids lacking a tyrosine mimetic

Abstract

The mu opioid agonist morphine is the standard for severe pain management. Despite the ability of morphine to treat severe pain, there are significant side effects which often cause undermedication in clinical settings. Such effects are respiratory depression, tolerance, constipation, and dependence. Accordingly, investigation of novel classes of opioid analgesics would provide great therapeutic benefits. 14-Phenylpropyloxymorphinans are agonists that exhibit extreme potency at mu receptors, suggesting that the 14-phenylpropyloxy group has a major effect on receptor binding and is responsible for the dramatic increase in potency. Our hypothesis is that both a basic amine and a phenylpropyloxy group alone are required for opioid activity, and the aromatic A-ring, that was historically considered essential, is not required. By removing the A-ring, this allows the skeleton to adopt an alternate binding mode with the receptor, thereby potentially causing alternate receptor trafficking events and post-receptor mechanisms, all of which are involved in the development of tolerance. During initial studies, a conformationally sampled pharmacophore approach was utilized to confirm that the aromatic moiety in the novel series does not mimic the A-ring. In order to further substantiate our hypothesis, a series of phenylpropyloxyethylamines and cinnamyloxyethylamines were synthesized, and analyzed for opioid receptor binding affinity. Opioid binding studies showed that the optimal N-substituent is the N-phenethyl, specifically analog 2-(cinnamyloxy)-N-methyl-N-phenethylethanamine which has an affinity of 1680 nM for mu opioid receptors. Subsequently, rings B, C, and D from the morphine skeleton were systematically re-introduced as ring-constrained analogs. Binding studies showed that the B-ring analog containing a N,N-dimethyl substituent produced the highest affinity of 2340 nM, while the C- and D-ring analogs were fully inactive. Furthermore, by combining the B-ring with the optimal N-substituent, phenethyl, we were able to achieve 1640 nM affinity at mu. Moreover, upon introduction of an indole group into the C-ring analog, N,N-dimethyl-1-(3-(3-phenylpropoxy)-2,3,4,9-tetrahydro-1H-carbazol-3-yl)methanamine, the affinity was increased to 1110 nM, which represents a viable lead compound for optimization studies.