Aporphines are naturally occurring alkaloids and possess diverse pharmacological effects including various central nervous system (CNS) receptors such as dopamine, serotonin and adrenergic receptors. Thus the aporphine scaffold can be considered to be a �privileged scaffold� for the design of new, potent and selective CNS receptor ligands, which can serve as valuable chemical probes to study receptor function in a variety of neuropsychiatric disorders. However, unexplored chemical space around the aporphine template needs to be systematically evaluated and exploited in order to make this ultimate goal a reality.Previous structure-activity relationship (SAR) studies with the aporphine alkaloid Nantenine, have resulted in the identification of a number of selective 5-HT2A receptor ligands via structural modifications at the C1, C2 and C3 positions.  Here we present work on continued SAR studies focusing on the C4 and N6 positions.The design of the C4 analogs was predicated on the hypothesis that the addition of a phenyl moiety to the C4 position of the aporphine template would engender enhanced affinity for 5-HT2A receptors (given the pharmacophoric similarity to known 5-HT2A ligands).  In case of the N6 analogs, the importance of the nitrogen atom for 5-HT2A affinity was evaluated via isosteric replacement with an oxygen atom to yield a novel isochroman-containing scaffold.  The compounds were evaluated for affinity at 5-HT2 receptor subtypes. Interestingly, the C4 analogs displayed a shift in selectivity towards the 5-HT2B receptor. The isochroman derivatives were devoid of affinity at 5-HT2 receptors, indicating that the nitrogen atom is required for affinity. Our results provide further insights into the structural features of aporphines for tolerance at 5-HT2 receptors. Furthermore, this work underscores the untapped potential of utilizing structurally diversified aporphines as novel, potent and selective 5-HT2 receptor ligands.  Details of our synthetic work and further extrapolations of SAR study will be presented.

Structural manipulations of aporphines en route to new chemical probes for CNS receptors

248th National Meeting (2014)

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