Bioorganic & Medicinal Chemistry Letters 14 (2004) 1913–1916
N-Acridin-9-yl-butane-1,4-diamine derivatives: high-affinity ligands
of the ꢀ2ꢁ subunit of voltage gated calcium channels
Jongwon Lim,a,*,y Nicholas Stock,a,y Richard Pracitto,a Julia K. Boueres,a
Benito Munoz,a Ashok Chaudhary,c Angelina M. Santini,b Karia Orr,b
Herve Schaffhauser,b Robert E. Bezverkov,b Jayashree Aiyarb
and Shankar Venkatramana
aDepartment of Chemistry, Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA
bDepartment of Neurobiology, Merck Research Laboratories, 3535 General Atomics Court, San Diego, CA 92121, USA
cDepartment of Drug Metabolism, Merck Research Laboratories, Rahway, NJ 07065, USA
Received 4 December 2003; revised 26 January 2004; accepted 28 January 2004
Abstract—A series of N-acridin-9-yl-butane-1,4-diamines were found to be high-affinity ligands of the a2d subunit of voltage gated
calcium channels. The SAR studies of butane-1,4-diamine side chain resulted in the identification of compound 10 (IC50=9 nM),
which is more potent than gabapentin (IC50=27 nM). Partial saturation of the acridine ring was also pursued and provided a
compound with higher binding affinity than 1.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
2. N4-Acridin-9-yl-N1,N1-diethyl-1-alkylbutane-
1,4-diamines
Gabapentin (Neurontin1), [1-(aminomethyl)cyclohexyl]-
acetic acid, is an anticonvulsant agent, and has been
shown to be effective against neuropathic pain both in
animal models and in human.1ꢀ5 The exact mechanism
of action of gabapentin in these therapeutic areas,
however, is still unclear. Recently, a high affinity
[3H]gabapentin-binding protein has been identified as
an a2d subunit of a voltage gated calcium channel, and
this subunit has been suggested to play an important
role in the pharmacological actions of gabapentin.6
First, we investigated the binding affinity of the enantio-
mers of 1, and found that the (S)-enantiomer 2 is the
active component (IC50=110 nM, Table 1). The stark
contrast in binding affinity between 2 and 3 suggests that
the methyl group of 1 is proximal to a binding pocket of
the protein, thereby the protein can differentiate the (S)
and (R) methyl groups. Secondly, the desmethyl analogue
4 is inactive whereas the gem-dimethyl analogue 5 is
almost as active as 2. Taken together these results
strongly suggest a specific interaction between the
ligands in this position and the protein.
Our goal was to discover novel gabapentin-mimetic
compounds, with which we can better understand the
mechanism of the pharmacological actions of gaba-
pentin and thereby develop more effective drugs. A
high-throughput screening campaign of [3H]gabapentin
binding in human brain membrane (A710 membrane)7
identified compound 1 as a high-affinity ligand of the
a2d subunit of a voltage gated calcium channel
(IC50=220 nM). Herein we report SAR studies on 1
and the discovery of highly potent ligands of the a2d
subunit of voltage gated calcium channels.
* Corresponding author. Tel.: +1-858-202-5731; fax: +1-858-202-
Both authors contributed equally to this work.
We next sought the optimal length of the side chain.
Preliminary SAR studies showed that all three nitrogen
y
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.087