APLINDORE (DAB-452) EXHIBITS HIGH
AFFINITY DOPAMINE D2 RECEPTOR PARTIAL
AGONIST ACTIVITY
M.Pausch,* J.N.Heinrich,M.Lai,K.Carroll,G.Hornby, M.Popiolek,L.Jiang,G.Stack,K.L.Marquis,
T.H.Andree
Discovery Neuroscience,Wyeth Research,Princeton,NJ,USA
The pharmacological properties of the dopamine D2 receptor (D2R)
partial agonist,aplindore (DAB-452),were characterized and com-
pared to other agents in this class. Aplindore exhibited high affinity
binding to both D2R short (D2RS) and long (D2RL) isoforms
expressed in membranes from stably transfected CHO_K1 cells.
Aplindore potently stimulated GTP?35S binding to D2RS and D2RL
containing membranes that was intermediate in efficacy between that
produced by the full D2R agonist quinpirole and the weak partial
agonist aripiprazole. CHO_K1 cells co-expressing either the D2RS
or the D2RL isoform and chimeric Gaq-proteins in which the C-ter-
minal five amino acids of inhibitory Ga-proteins (Gao, Gai1, -2,
Gai3) were substituted onto the full length Gaq,facilitated detection
of intracellular calcium increase ([Ca2+]i) measured by fluorometric
imaging plate reader (FLIPR) technology. Agonist dose-dependent
responses were observed with efficacy profile (quinpirole =
dopamine = pramipexole > aplindore > (+/-) 3-PPP > (-) 3-PPP >
aripiprazole > SDZ-208-912) and rank-order-of-potency (dopamine
= quinpirole = pramipexole = aplindore > (+/-) 3-PPP > (-) 3-PPP >
aripiprazole > SDZ-208-912) that were similar for both D2R iso-
forms. The sensitivity and high-throughput capacity of the FLIPR
assay provides a convenient approach to explore the partial agonist
pharmacology of D2R-ligands and may facilitate discovery of com-
pounds with enhanced therapeutic properties. <<
From "ABSTRACTS OF THE XX INTERNATIONAL CONGRESS
ON SCHIZOPHRENIA RESEARCH
April 2–April 6,2005,Savannah,Georgia"
>>Heinrich JN, Brennan J, Lai MH, Sullivan K, Hornby G, Popiolek M, Jiang LX, Pausch MH, Stack G, Marquis KL, Andree TH
Aplindore (DAB-452), a high affinity selective dopamine D2 receptor partial agonist.
Eur J Pharmacol. 2006 Dec 15;552(1-3):36-45.
The pharmacology of aplindore (DAB-452) was characterized in CHO-K1 cells stably transfected with the human dopamine D(2) receptor short isoform (CHO-D(2s)) and in a behavioral model for post-synaptic agonism in rats. In [(3)H]-spiperone competition binding studies, aplindore showed high affinity for dopamine D(2) and D(3) receptors and low affinity for the dopamine D(4), serotonin (5-HT)(1A), 5-HT(2) receptors and the alpha1-adrenoceptor. The high potency partial agonist activity of aplindore was demonstrated in [(35)S]guanosine 5'-O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding, extracellular signal-regulated kinase (ERK)-phosphorylation and intracellular calcium flux assay using fluorometric plate reader ([Ca(2+)](i)-FLIPR) format. The [Ca(2+)](i)-FLIPR assay was conducted with CHO-D(2S) receptor cells also stably expressing chimeric G(alphaq/o)-proteins. In all assay modalities, the potencies and intrinsic activities of aplindore were lower than dopamine and higher than aripiprazole. In contrast to the [(35)S]GTPgammaS binding and ERK-phosphorylation assays, the [Ca(2+)](i)-FLIPR assay was able to detect the low partial agonist activity of SDZ 208-912. In unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, aplindore induced contralateral turning, which was blocked by the dopamine D(2) receptor antagonist raclopride. The dopamine D(2) receptor selective partial agonist profile of aplindore suggests that it should be effective for the treatment of dopaminergic-based disorders, such as schizophrenia and Parkinson's disease.<<
Wyeth hasn't released dosages as far as I can tell. Maybe NRGN said something on the CC about that?
Cheers, Tuck |
