Synthesis of Enantiopure Nantenine Analogs as Serotonin 5-HT2A Receptor Antagonists
Nantenine is an aporphine natural product that antagonizes the behavioral and physiological effects of the designer drug MDMA, or “ecstasy.” MDMA binds to G protein-coupled receptors in the CNS (such as 5-HT2A and α1A receptors) that induce the downstream release of serotonin and loss of receptors associated with MDMA abuse. (±)-Nantenine is a selective α1A receptor (Ke = 36 nM) antagonist with moderate 5-HT2A receptor antagonist potency (Ke = 850 nM). We hypothesize that structural modifications to the aporphine scaffold of nantenine will allow for the identification of more potent 5-HT2A and α1A receptor antagonists. Such molecules will be useful to investigate in vivo as potential MDMA antagonists.
Previous structure-activity relationship (SAR) studies indicate that lipophilic groups at the C1 position or bromination of the C3 position significantly improves 5-HT2A receptor antagonism (up to 15-fold). Since these studies were conducted with racemic analogs, the extent to which the sole chiral center of the aporphine template impacts 5-HT2A receptor antagonism is not known. Encouraged by these findings and spurred by deficits in prior SAR work, our goal is to design and synthesize a series of new enantiopure nantenine derivatives bearing a C1 lipophilic substituent in tandem with a C3 halogen substituent. Biological evaluation of enantiomeric analogs will shed light on the desired configuration of the chiral center for eutomeric 5-HT2A receptor antagonism. Furthermore, we anticipate that the new molecules will exhibit enhanced 5-HT2A receptor antagonist potency and concomitant anti-MDMA effects as compared to earlier generations of C1 and C3 (±)-nantenine derivatives.