ADX-88178 [5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine] is a small molecule positive
allosteric modulator (PAM) of metabotropic glutamate receptor subtype 4
(mGluR4; GRM4). The molecule is selective for mGluR4, orally available, brain
penetrant and has the potential to ameliorate Parkinsonian symptoms. Addex has
reported ADX88178 as a novel mGluR4 PAM and demonstrated its efficacy in
several different rodent models of Parkinson’s disease [1].
The activity of ADX88178 is as
follows:
EC50 (human
mGluR4, FLIPR assay) = 3.5 ± 0.3 nM
EC50 (rat mGluR4, FLIPR assay) =
9.1 ±
1.0 nM
Ki (human mGluR4, Binding assay) = 39
nM
Common Name: ADX-88178
Synonyms: ADX88178; ADX 88178; ADX-88178
IUPAC Name: 5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)-1,3-thiazol-2-amine
CAS Number: 1235318-89-4
SMILES: CC1=NC(=NC=C1)NC2=NC(=C(S2)C)C3=CNN=C3
Mechanism of Action: Metabotropic glutamate receptor (mGluR)
modulator
Indication: Treatment for Parkinson’s disease; Treatment for PD
Development Stage: Preclinical
Company: Addex Therapeutics Ltd.
Parkinson’s disease or PD (also known as
idiopathic, or primary parkinsonism, hypokinetic rigid syndrome (HRS) or
paralysis agitans) is a degenerative disorder of the central nervous system
mainly affecting the motor system. The motor symptoms of Parkinson’s disease
result from the death of dopamine-generating cells in the substantia nigra (SN,
a region in the mid brain). As a consequence of the depletion of dopamine, a
series of movement disorders appear, including bradykinesia, akinesia, tremor,
gait disorders and problems with balance. These motor disturbances form the
hallmark of Parkinson’s disease, although there are many other non-motor
symptoms also that are associated with the disease, such as sensory, sleep and
emotional problems. PD is more common in older people, with most cases
occurring after the age of 50. When the symptoms are observed in young adults,
it is called young onset PD (YOPD). In the early course of the disease,
symptoms can be effectively treated by dopamine replacement or augmentation
with the use of dopamine D2 receptor agonists, such as levodopa or monoamine
oxidase B inhibitors. But, as the disease progresses these agents become less
effective in controlling motor symptoms. Also, the use of these agents is
limited by the emergence of adverse effects including dopamine agonist-induced
dyskinesias. Therefore, activation of metabotropic glutamate receptor 4
(mGluR4) has been proposed as a potential therapeutic approach to treat
Parkinson’s disease [2, 3, 4].
The metabotropic glutamate receptor 4 (mGlu4)
belongs to the Group III mGluRs (Class C G-Protein Coupled Receptor) and is
negatively coupled to adenylate cyclase via activation of the Gai/o protein. It
is expressed primarily on presynaptic terminals, functioning as an autoreceptor
or heteroceptor and its activation leads to decreases in transmitter release
from presynaptic terminals. MGlu4 is currently receiving much attention based
primarily upon its unique distribution in key brain region involved in many CNS
disorders. MGlu4 PAM is emerging as a promising target for the treatment of
motor and non-motor symptoms as well as a disease-modifying agent in
Parkinson`s disease through a non-dopaminergic approach.
Symptoms of Parkinson’s disease are believed to
be due to progressive death of dopaminergic. Reduction in dopaminergic
neurotransmission leads to an imbalance in the direct and indirect output
pathways of the basal ganglia. Reduction of transmission at the inhibitory
GABAergic striato-pallidal synapse in the indirect pathway is believed to
result in alleviation of these symptoms. mGluR4 is abundant in striato-pallidal
synapses. Its localization suggests it functions as a presynaptic
heteroreceptor on GABAergic neurons, suggesting in turn that selective
activation or positive modulation of mGluR4 would decrease GABA release in this
synapse, thereby decreasing output of the indirect pathway and reducing or
eliminating the PD symptoms.
In vitro properties of ADX88178 were evaluated by monitoring calcium
mobilization in HEK293 cell lines modified to express human and rat mGluR4.
ADX88178 was also evaluated in a radioligand binding assay with human mGluR4
receptors obtained from membranes from the HEK293 cell line. The compound
completely displaced the specific binding of [3H]PAM2, a
structurally distinct compound in this assay. When investigated for its
selectivity for mGluR4, ADX88178 exhibited no effect on mGluR1, 2, 3, 5, 7 or
GABAB at concentrations upto 30 uM. Agonist activity at mGluR6
was detected with an EC50 value greater than10 uM, while the
compound acted as a PAM at mGluR8 with an EC50 of 2.2 uM. The
compound was found to be inactive at 10 uM when screened against other
receptors, transporters, enzymes and ion channels in the Cerep panel, except
human adenosine A1 and A3 [1].
ADX88178 reverses haloperidol induced catalepsy
(HIC) in rats at 3 and 10 mg/kg after oral administration. More importantly,
the combination of ADX88178 (3, 10 and 30 mg/Kg, p.o.) with a low dose of L-DOPA enabled a robust, dose-dependent
reversal of the forelimb akinesia deficit induced to a bilateral 6-OHDA lesion
of the striatum in rats. In addition, co-administration of ADX88178 (10 mg/kg,
p.o.) did not worsen dyskinesia induced by L-DOPA in rats subjected to a
unilateral 6-OHDA lesion of the medial forebrain bundle. This is consistent
with an L-DOPA sparing action that may prove to be therapeutically useful for
the management of motor symptoms of PD.
References:
1. Le Poul, E.; et. al. A potent and selective
metabotropic glutamate receptor 4 positive allosteric modulator improves
movement in rodent models of Parkinson’s disease. J Pharmacol Exp Ther 2012, 43(1), 167-177.
2. Marino, M. J.; et. al. Allosteric modulation of group
III metabotropic glutamate receptor 4: a potential approach to Parkinson’s
disease treatment. Proc Natl Acad
Sci USA 2003, 100(23), 13668-13673.
3. Marino, M. J.; et. al. Glutamate-based therapeutic
approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol 2006, 6(1),
98-102.
4. Duty, S. Therapeutic
potential of targeting group III metabotropic glutamate receptors in the
treatment of Parkinson’s disease. Br
J Pharmacol 2010, 161(2), 271-287.
