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Synthesis and Pharmacological Evaluation of DH?E Analogues as Neuronal Nicotinic Acetylcholine Receptor Antagonists.

ABSTRACT: Dihydro-?-erythroidine (DH?E) is a member of the Erythrina family of alkaloids and a potent competitive antagonist of the ?4?2-subtype of the nicotinic acetylcholine receptors (nAChRs). Guided by an X-ray structure of DH?E in complex with an ACh binding protein, we detail the design, synthesis, and pharmacological characterization of a series of DH?E analogues in which two of the four rings in the natural product has been excluded. We found that the direct analogue of DH?E maintains affinity for the ?4?2-subtype, but further modifications of the simplified analogues were detrimental to their activities on the nAChRs.

SUBMITTER: Jepsen TH 

PROVIDER: S-EPMC4094251 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Jepsen Tue Heesgaard TH   Jensen Anders A AA   Lund Mads Henrik MH   Glibstrup Emil E   Kristensen Jesper Langgaard JL  

ACS medicinal chemistry letters 20140520 7

Dihydro-β-erythroidine (DHβE) is a member of the Erythrina family of alkaloids and a potent competitive antagonist of the α4β2-subtype of the nicotinic acetylcholine receptors (nAChRs). Guided by an X-ray structure of DHβE in complex with an ACh binding protein, we detail the design, synthesis, and pharmacological characterization of a series of DHβE analogues in which two of the four rings in the natural product has been excluded. We found that the direct analogue of DHβE maintains affinity for  ...[more]

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