Synthesis and pharmacological evaluation of DHβE analogs as neuronal nicotinic acetylcholine receptor antagonists

TY - JOUR

T1 - Synthesis and pharmacological evaluation of DHβE analogs as neuronal nicotinic acetylcholine receptor antagonists

AU - Jepsen, Tue H.

AU - Jensen, Anders A.

AU - Lund, Mads Henrik

AU - Glibstrup, Emil

AU - Kristensen, Jesper Langgaard

PY - 2014/7/10

Y1 - 2014/7/10

N2 - 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 the α4β2-subtype, but further modifications of the simplified analogues were detrimental to their activities on the nAChRs.

AB - 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 the α4β2-subtype, but further modifications of the simplified analogues were detrimental to their activities on the nAChRs.

U2 - 10.1021/ml500094c

DO - 10.1021/ml500094c

M3 - Journal article

C2 - 25050162

SN - 1948-5875

VL - 5

SP - 766

EP - 770

JO - ACS Medicinal Chemistry Letters

JF - ACS Medicinal Chemistry Letters

IS - 7

ER -