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. 2018 Jan 22;9(2):353-356.
doi: 10.1039/c7md00656j. eCollection 2018 Feb 1.

Discovery of 7-hydroxyaporphines as conformationally restricted ligands for beta-1 and beta-2 adrenergic receptors

Angela F Ku  1 , Gregory D Cuny  1
Affiliations

Discovery of 7-hydroxyaporphines as conformationally restricted ligands for beta-1 and beta-2 adrenergic receptors

Angela F Ku et al. Medchemcomm. .

Abstract

A series of (-)-nornuciferidine derivatives was synthesized and the non-natural enantiomer of the aporphine alkaloid was discovered to be a potent β1- and β2-adrenergic receptor ligand that antagonized isoproterenol and procaterol induced cyclic AMP increases from adenylyl cyclase, respectively. Progressive deconstruction of the tetracyclic scaffold to less complex cyclic and acyclic analogues revealed that the conformationally restricted (6a-R,7-R)-7-hydroxyaporphine 2 (AK-2-202) was necessary for efficient receptor binding and antagonism.

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Figures

Fig. 1
Fig. 1. Examples of β2-AR ligands and the 7-hydroxyaporphine scaffold; β2-AR pharmacophore elements highlighted in red for ethanolamine and blue for the aromatic ring.
Scheme 1
Scheme 1. Summarized synthetic routes for compounds 1–5.
Scheme 2
Scheme 2. Synthetic route for compound 6.
See this image and copyright information in PMC

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