Alofropodect is an orally active, blood-brain barrier permeable phosphodiesterase 10A ( PDE10A ) inhibitor with IC50 values of 1 nM (Reference 1) and 35 nM (Reference 2). Alofropodect acts as a negative allosteric modulator of the M2 muscarinic receptor with an IC50 of 9.2 μM. Alofropodect alters cyclic nucleotide levels in basal ganglia circuits, inhibits the hydrolysis of cAMP and cGMP, and suppresses hERG potassium channel tail currents. Alofropodect induces catalepsy in rats and reverses injury-induced contralateral forelimb use impairment. Alofropodect can be used in research related to schizophrenia, Parkinson's disease, and levodopa-induced dyskinesia [1] [2].
In Vivo, Alofropodect (0.15-2 mg/kg; p.o.; single administration) induces dose-dependent catalepsy in male Sprague-Dawley rats[1]. Alofropodect (0.1-0.3 mg/kg; p.o.; single acute administration combined with Levodopa /Benserazide for 16 consecutive days) dose-dependently improves sensorimotor deficits in 6-hydroxydopamine-lesioned rats[2].
In Vitro, Alofropodect (0.1-10 μM; 5 min) inhibits hERG tail current in hERG-HEK-293 transfected cells with an IC25 of 3.2 μM[1]. Alofropodect (0.0457-100 μM; 14 days) does not affect key cardiac spheroid health parameters up to 100 μM, but impairs DNA structure with an IC50 of 37.4 μM in human pluripotent cell-derived 3D cardiac spheroids[1]. Alofropodect (8 nM-60 μM; 72 h) is not cytotoxic at concentrations up to 60 μM in NCI-H1299, HepG2, and SH-SY5Y cell lines[1].
References:
[1]. Matloka M, et al. A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects. Front Pharmacol. 2022;13:999685. Published 2022 Nov 9.
[2]. Lenda T, et al. Antiparkinsonian-like effects of CPL500036, a novel selective inhibitor of phosphodiesterase 10A, in the unilateral rat model of Parkinson's disease. Eur J Pharmacol. 2021;910:174460.
In Vivo, Alofropodect (0.15-2 mg/kg; p.o.; single administration) induces dose-dependent catalepsy in male Sprague-Dawley rats[1]. Alofropodect (0.1-0.3 mg/kg; p.o.; single acute administration combined with Levodopa /Benserazide for 16 consecutive days) dose-dependently improves sensorimotor deficits in 6-hydroxydopamine-lesioned rats[2].
In Vitro, Alofropodect (0.1-10 μM; 5 min) inhibits hERG tail current in hERG-HEK-293 transfected cells with an IC25 of 3.2 μM[1]. Alofropodect (0.0457-100 μM; 14 days) does not affect key cardiac spheroid health parameters up to 100 μM, but impairs DNA structure with an IC50 of 37.4 μM in human pluripotent cell-derived 3D cardiac spheroids[1]. Alofropodect (8 nM-60 μM; 72 h) is not cytotoxic at concentrations up to 60 μM in NCI-H1299, HepG2, and SH-SY5Y cell lines[1].
References:
[1]. Matloka M, et al. A PDE10A inhibitor CPL500036 is a novel agent modulating striatal function devoid of most neuroleptic side-effects. Front Pharmacol. 2022;13:999685. Published 2022 Nov 9.
[2]. Lenda T, et al. Antiparkinsonian-like effects of CPL500036, a novel selective inhibitor of phosphodiesterase 10A, in the unilateral rat model of Parkinson's disease. Eur J Pharmacol. 2021;910:174460.