J. Am. Chem. Soc. 2000, 122, 5393-5394
Application of the Bivalent Ligand Approach to the
5393
Design of Novel Dimeric Serotonin Reuptake
Inhibitors
Amir P. Tamiz,† Jianrong Zhang,† Mei Zhang,‡
Cheng Z. Wang,‡ Kenneth M. Johnson,‡ and
Alan P. Kozikowski*,†
Drug DiscoVery Program
Georgetown UniVersity Medical Center
3970 ReserVoir Road, NW, Washington, D.C. 20007-219
Department of Pharmacology and Toxicology
UniVersity of Texas Medical Branch
GalVeston, Texas 77555-1031
ReceiVed January 18, 2000
Figure 1. (A) Model for the binding of a bivalent ligand of appropriate
chain length to neighboring recognition sites. Given the proper linker
geometry, the bivalent binding is favored. (B) Model binding of bivalent
neighboring recognition sites with a bivalent ligand with an inadequate
chain length. Only univalent binding is possible.12b
Chemical modulation of the monoamine neurotransmitter
systems involving dopamine (DA), serotonin (5-HT), and nore-
pinephrine (NE) provides an important means to control certain
neurological disorders such as depression,1 anxiety,2 alcoholism,3
chronic pain,4 eating disorders,5 and obsessive compulsive
disorders.6 For example, a major pharmaceutical approach to the
treatment of depression has come about through the development
of agents that interfere with the primary mechanism of removal
of 5-HT or NE from the synapse.7 As the result, the selective
5-HT reuptake inhibitors (SSRIs) such as fluoxetine (Prozac)8
and paroxetine (Paxil),9 among others, have been developed for
the treatment of depression and related psychological disorders.
Despite these recent clinical developments, a detailed understand-
ing of the structural factors that govern the potency and selectivity
of ligands at the specific monoamine transporters is still evolving.
During our efforts to discover ligands of possible use as
medications,10 we discovered a rather interesting aspect of the
5-HT transporter (SERT) structure activity relationships (SAR),
namely that significant selectivity and potency can be achieved
through the use of a bivalent ligand approach (Figure 1).
The rationale for employing the bivalent ligand approach stems
from the possibility that dimeric structures may be capable of
bridging independent recognition sites on the transporters resulting
in a thermodynamically more favorable binding interaction than
the monovalent binding of two molecules.11 As such proximal
binding sites are likely to differ in their location for the three
monoaminergic transporters the length of the linker connecting
the two binding moieties could thus provide a means to fine-
tune transporter selectivity profiles. Empirical support for such a
possibility stems from the enhanced potency and selectivity
reported for both bivalent narcotic antagonists containing the
naltrexamine pharmacophore12 and for serotonin-based bivalent
5-HT1B/1D agonists.13
We have recently reported on the chemistry and pharmacology
of some 3,4-disubstituted piperidine-based ligands that show
reasonable potency at the dopamine transporter (DAT).14 On the
basis of these and other studies15 it had become apparent to us
that 3,4-disubstituted piperidines are structurally related to drugs
such as femoxetine and paroxetine that exhibit high potency and
selectivity for the SERT.16 One of these piperidines was therefore
chosen as the starting monomer for the assembly of bivalent
ligands that were postulated to exhibit potent and selective SERT
activity.
Briefly, piperidine-based ligands 4-16 were prepared in
optically pure form from arecoline (1)14 (Scheme 1) and were
evaluated for their ability to inhibit high affinity uptake of DA,
5-HT, and NE using rat synaptosomal nerve endings.17 The uptake
data expressed as Ki values and the selectivity profile (ratio of Ki
values) for these compounds are provided in Table 1. In general,
all dimers (7-16) exhibit substantially higher potency at the SERT
than their monomeric counterparts. As is apparent from Table 1,
the SERT and the DAT potency increase of the bivalent ligand
11 over the monovalent ligand 3 is greater than a factor of 2.
However, the NET activity of compound 11 is slightly decreased,
as the bivalent inhibitor may undergo univalent binding at high
concentrations (Figure 1B). Therefore, the presence of a five-
methylene spacer in the linking chain of 11 appears to favor
bivalent binding at the SERT and the DAT (Figure 1, model A).
Specifically, the potency of piperidine 11, a bivalent analogue of
the parent piperidine 3, has improved by a factor of greater than
† Georgetown University Medical Center
‡ University of Texas Medical Branch
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10.1021/ja000199f CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/18/2000