PD 102807

PD 102807 is a M4 muscarinic receptor antagonist with an IC50 of 90.7 nM. PD 102807 inhibits M1, M2, M3, M5 muscarinic receptor with IC50s of 6558.7, 3440.7, 950.0, and 7411.7 nM, respectively[1]. Antidyskinetic effect.

Signaling Pathways >> Neuronal Signaling >> mAChR

Signaling Pathways >> GPCR/G Protein >> mAChR

Research Areas >> Neurological Disease

PD 102807 (example 1) shows selectivity for M4 muscarinic receptor with 72-fold (M1), 38-fold (M2), 10-fold (M3), and 82-fold (M5) more selective compared to the other receptors[1]. PD 102807, a novel M4 selective antagonist, counteracts the M4 receptor-induced stimulation of [35S]-GTPγS binding to membrane G proteins with a pKB of 7.40, a value which is 63-, 33- and 10-fold higher than those display at M1 (pKB=5.60), M2 (pKB=5.88) and M3 (pKB=6.39) receptor subtypes, respectively[2]. PD-102807 is an M4 mAChR preferring antagonist, with 7-28 nM affinity for M4 mAChRs, a 14-36-fold selectivity for M4 over M3 mAChRs, and 76-2600-fold selectivity for M4 over M1, M2 and M5 mAChRs[3].

Striatal perfusion of PD-102807 (3 μM) alleviates levodopa-induced dyskinesia (LID) and inhibits nigral GABA and Glu along with striatal Glu release[3]. Animal Model: Male Sprague-Dawley rats[3] Dosage: 3 μM Administration: Administration:Perfusion started 40 min prior to L-DOPA (6 mg/Kg plus 12 mg/Kg benserazide, s.c.) administration and continued until the end of experiment. Result: Basal dialysate levels in PD-102807 experiment were 19.19±2.62 nM and 47.77±3.42 nM for GABA and Glu in SNr, respectively, and 41.38±4.25 nM for Glu in striatum. Reduced global Axial Limb Orolingual (ALO) Abnormal Involuntary Movements (AIM) expression from 70.75±5.64 to 25.38±6.64, significantly attenuating limb, axial and orolingual AIMs at 3 μM. Inhibited the L-DOPA-induced rise of substantia nigra pars reticulata (SNr) GABA, SNr Glu, and striatal Glu at 3 μM.

[1]. C E Augelli-Szafran, et al. Identification and characterization of m4 selective muscarinic antagonists. Bioorg Med Chem Lett. 1998 Aug 4;8(15):1991-6.

[2]. M C Olianas, et al. PD 102807, a novel muscarinic M4 receptor antagonist, discriminates between striatal and cortical muscarinic receptors coupled to cyclic AMP. Life Sci. 1999;65(21):2233-40.

[3]. Alberto Brugnoli, et al. Striatal and nigral muscarinic type 1 and type 4 receptors modulate levodopa-induced dyskinesia and striato-nigral pathway activation in 6-hydroxydopamine hemilesioned rats. Neurobiol Dis. 2020 Oct;144:105044.