Pimavanserin

Pimavanserin is a selective, brain-penetrant, inverse agonist of the 5-HT2A receptor with pIC₅₀ and pK_d of 8.73 and 9.3, respectively. IC50 & Target:pIC50: 8.7 (5-HT_2A)^[1] In Vitro:Pimavanserin (ACP-103) competitively antagonizes the binding of [³H]ketanserin to heterologously expressed human 5-HT_2A receptors with a mean pK_i of 9.3 in membranes and 9.70 in whole cells. Pimavanserin demonstrates lesser affinity (mean pK_i of 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC₅₀ 7.1 in R-SAT) at human 5-HT_2C receptors, and lacked affinity and functional activity at 5-HT_2B receptors, dopamine D₂ receptors, and other human monoaminergic receptors^[1]. Pimavanserin (ACP-103) is highly selective for 5-HT_2A receptors, lacking affinity for other receptors in a broad profile screen including 65 different molecular targets; the only other receptor for which Pimavanserin demonstrates affinity is 5-HT_2C, and Pimavanserin is approximately 30-fold selective for 5-HT_2A receptors over 5-HT_2C receptors depending on the assay^[2]. In Vivo:Pimavanserin (ACP-103) is a potent, efficacious, orally active 5-HT_2A receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent. Pimavanserin attenuates head-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT_2A receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduces the hyperactivity induced in mice by the N-methyl-D-aspartate receptor noncompetitive antagonist 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate; MK-801) (0.1 and 0.3 mg/kg s.c.; 3 mg/kg p.o.), consistent with a 5-HT_2A receptor mechanism of action in vivo and antipsychotic-like efficacy. Pimavanserin demonstrates >42.6% oral bioavailability in rats^[1].