Synthesis and Pharmacological Evaluation of DHßE Analogues as Neuronal Nicotinic Acetylcholine Receptor Antagonists.

Dihydro-ß-erythroidine (DHßE) is a member of the Erythrina family of alkaloids and a potent competitive antagonist of the α4ß2-subtype of the nicotinic acetylcholine receptors (nAChRs). Guided by an X-ray structure of DHßE in complex with an ACh binding protein, we detail the design, synthesis, and pharmacological characterization of a series of DHßE analogues in which two of the four rings in the natural product has been excluded. We found that the direct analogue of DHßE maintains affinity for the α4ß2-subtype, but further modifications of the simplified analogues were detrimental to their activities on the nAChRs.