From α4β2 nicotinic ligands to the discovery of σ1 receptor ligands: Pharmacophore analysis and rational design

Li Fang Yu; Han Kun Zhang; Hendra Gunosewoyo; Alan P. Kozikowski

doi:10.1021/ml3002715

From α4β2 nicotinic ligands to the discovery of σ1 receptor ligands: Pharmacophore analysis and rational design

Li Fang Yu, Han Kun Zhang, Hendra Gunosewoyo, Alan P. Kozikowski

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Comparative analyses of the pharmacophoric elements required for σ1 and nicotinic ligands led to the identification of a potent and selective σ1 ligand (15). Compound 15 displayed high selectivity for the σ1 receptor (K_i, σ1 = 4.1 nM; K_i, σ2 = 1312 nM) with moderate binding affinity for the DAT (K_i = 373 nM) and NET (K_i = 203 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. The key finding in this present work is that a subtle structural modification could be used as a tool to switch a ligand's selectivity between nAChRs and sigma receptors.

Original language	English (US)
Pages (from-to)	1054-1058
Number of pages	5
Journal	ACS Medicinal Chemistry Letters
Volume	3
Issue number	12
DOIs	https://doi.org/10.1021/ml3002715
State	Published - Dec 13 2012
Externally published	Yes

Keywords

Nicotinic acetylcholine receptor
alkoxyisoxazole
broad screening
pharmacophore
sigma-1 receptor

ASJC Scopus subject areas

Biochemistry
Drug Discovery
Organic Chemistry

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10.1021/ml3002715

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abstract = "Comparative analyses of the pharmacophoric elements required for σ1 and nicotinic ligands led to the identification of a potent and selective σ1 ligand (15). Compound 15 displayed high selectivity for the σ1 receptor (Ki, σ1 = 4.1 nM; Ki, σ2 = 1312 nM) with moderate binding affinity for the DAT (Ki = 373 nM) and NET (Ki = 203 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. The key finding in this present work is that a subtle structural modification could be used as a tool to switch a ligand's selectivity between nAChRs and sigma receptors.",

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T2 - Pharmacophore analysis and rational design

AU - Yu, Li Fang

AU - Zhang, Han Kun

AU - Gunosewoyo, Hendra

AU - Kozikowski, Alan P.

PY - 2012/12/13

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AB - Comparative analyses of the pharmacophoric elements required for σ1 and nicotinic ligands led to the identification of a potent and selective σ1 ligand (15). Compound 15 displayed high selectivity for the σ1 receptor (Ki, σ1 = 4.1 nM; Ki, σ2 = 1312 nM) with moderate binding affinity for the DAT (Ki = 373 nM) and NET (Ki = 203 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. The key finding in this present work is that a subtle structural modification could be used as a tool to switch a ligand's selectivity between nAChRs and sigma receptors.

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KW - pharmacophore

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From α4β2 nicotinic ligands to the discovery of σ1 receptor ligands: Pharmacophore analysis and rational design

Abstract

Keywords

ASJC Scopus subject areas

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