N-Acridin-9-yl-butane-1,4-diamine derivatives: high-affinity ligands of the alpha2delta subunit of voltage gated calcium channels

Jongwon Lim; Nicholas Stock; Richard Pracitto; Julia K Boueres; Benito Munoz; Ashok Chaudhary; Angelina M Santini; Karia Orr; Hervé Schaffhauser; Robert E Bezverkov; Jayashree Aiyar; Shankar Venkatraman

doi:10.1016/j.bmcl.2004.01.087

N-Acridin-9-yl-butane-1,4-diamine derivatives: high-affinity ligands of the alpha2delta subunit of voltage gated calcium channels

Bioorg Med Chem Lett. 2004 Apr 19;14(8):1913-6. doi: 10.1016/j.bmcl.2004.01.087.

Authors

Jongwon Lim¹, Nicholas Stock, Richard Pracitto, Julia K Boueres, Benito Munoz, Ashok Chaudhary, Angelina M Santini, Karia Orr, Hervé Schaffhauser, Robert E Bezverkov, Jayashree Aiyar, Shankar Venkatraman

Affiliation

¹ Department of Chemistry, Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA. jongwon_lim@merck.com

PMID: 15050626
DOI: 10.1016/j.bmcl.2004.01.087

Abstract

A series of N-acridin-9-yl-butane-1,4-diamines were found to be high-affinity ligands of the alpha(2)delta subunit of voltage gated calcium channels. The SAR studies of butane-1,4-diamine side chain resulted in the identification of compound 10 (IC(50)=9 nM), which is more potent than gabapentin (IC(50)=27 nM). Partial saturation of the acridine ring was also pursued and provided a compound with higher binding affinity than 1.

MeSH terms

Acetates / pharmacology
Amines*
Binding, Competitive / drug effects
Calcium Channels / drug effects
Calcium Channels / physiology*
Cyclohexanecarboxylic Acids*
Diamines / chemical synthesis
Diamines / chemistry*
Diamines / pharmacology*
Gabapentin
Ligands
Molecular Structure
Protein Binding / drug effects
Protein Binding / physiology
Protein Subunits / drug effects
Protein Subunits / physiology*
Structure-Activity Relationship
gamma-Aminobutyric Acid*

Substances

Acetates
Amines
Calcium Channels
Cyclohexanecarboxylic Acids
Diamines
Ligands
Protein Subunits
gamma-Aminobutyric Acid
Gabapentin