Bioorganic & Medicinal Chemistry Letters
Synthesis and binding profile of haloperidol-based bivalent ligands
targeting dopamine D2-like receptors
Ismail Salama a,b, Stefan Löber a, Harald Hübner a, Peter Gmeiner a,
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a Department of Medicinal Chemistry, Emil Fischer Center, Friedrich-Alexander University, Schuhstraße 19, D-91052 Erlangen, Germany
b Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Suez Canal University, 41522 Ismailia, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
Homodimers of dopamine D2-like receptors are suggested to be of particular importance in the patho-
physiology of schizophrenia and, thus, serve as promising targets for the discovery of atypical antipsy-
Received 14 May 2014
Revised 24 June 2014
Accepted 26 June 2014
Available online 3 July 2014
chotics. This study describes the development of
a series of novel bivalent molecules with a
pharmacophore derived from the dopamine receptor antagonist haloperidol. These dimers were investi-
gated in comparison to their monomeric analogues for their D2long, D2short, D3, and D4 receptor binding
and the ability to bridge two neighboring receptor protomers. Radioligand binding studies provided diag-
nostic insights when Hill slopes close to two for the bivalent ligand 13 incorporating 22 spacer atoms and
a comparative analysis with monovalent control ligands indicated a bivalent binding mode with a simul-
taneous occupancy of two neighboring binding sites.
Keywords:
Bivalent ligands
Dopamine
Binding affinity
GPCR dimers
D2 receptor
D3 receptor
D4 receptor
Ó 2014 Elsevier Ltd. All rights reserved.
G-protein-coupled receptors (GPCRs) are transmembrane
receptors that mediate most of their intracellular actions
through pathways involving an activation of G-proteins.1 Because
GPCR-promoted signaling is involved in a great number of patho-
physiological processes, members of this large family of proteins
are targeted most frequently at the development of therapeutics
for numerous diseases.2,3
Employing the antipsychotic drugs haloperidol and haloperidol
decanoate as lead compounds,20 we envisioned to synthesize and
biologically investigate dimeric derivatives thereof. Thus, we
designed a prototypical structure of bivalent molecules using poly-
methylene moieties or triazolyl-linked spacer elements, which
were bound via carboxylate functions to the tertiary alcohol group
of the pharmacophore unit. Subsequent radioligand binding stud-
ies indicated a bivalent binding mode with a simultaneous occu-
pancy of two adjacent binding sites when Hill slopes close to two
were observed for the test compound 13 comprising a 22-atom
spacer length.
A selection of spacer groups have been reported in the litera-
ture, varying from polymethylene, polyamide, polyethyleneglycol,
polyproline, and piperazine containing moieties, all with differing
degrees of flexibility and lipophilicity. Designing a collection of
homobivalent dopamine receptor ligands, we incorporated either
methylene or ethylene glycol units with or without triazole or
piperazine rings to build spacers with a length varying from 4 to
26 atoms.
Several lines of evidence suggest that some GPCRs including
5,6
7
D1,4 D2 and D3 receptors may exist in dimeric or oligomeric
form modulating ligand pharmacology, signal transduction and
cellular trafficking.8 Using functional complementation assays,
communication between protomers of the D2 receptors could be
observed leading to a significant modulation of GPCR activation
in transfected cell lines.9 According to very recent findings,10
homodimers of dopamine D2-like receptors might be of particular
importance in the pathophysiology of schizophrenia serving as
promising targets for the discovery of atypical antipsychotics.
Bivalent ligands11–14 were developed consisting of two pharma-
cophore moieties connected by a spacer with an appropriate length
allowing the two head groups to interact with two orthosteric
binding sites of adjacent receptors of a dimer or with another rel-
evant allosteric site at the same protomer.15–19
For comparative purposes, monovalent fragments containing
one-half of the linker were synthesized for selected compounds.
The bivalent ligands 1–13 were synthesized by treatment of halo-
peridol with dicarboxylic acid chlorides of varying length in pres-
ence of DIPEA to give the bis-haloperidol derivatives bearing
ester functionalities at their point of attachment (Scheme 1).
Analogously, the respective monovalent compounds 14–17 were
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0960-894X/Ó 2014 Elsevier Ltd. All rights reserved.