5-HT7/5-HT2A receptor antagonist 1 is a high-affinity, orally active compound capable of crossing the blood-brain barrier, serving as a ligand for both 5-HT7 and 5-HT2A receptors with a pKi of 8.1 at each receptor. It acts as an antagonist in vitro in 5-HT2A functional assays and as an inverse agonist in 5-HT7 functional assays. This compound blocks hypothermia in rats induced by 5-Carboxamidotryptamine (5-CT) and prevents head twitches in mice caused by 2,5-Dimethoxy-4-iodoamphetamine (DOI). Additionally, it occupies 5-HT2A receptor binding sites in the frontal cortex of rat brains and is applicable in the study of neurological disorders.

5-HT7/5-HT2A receptor antagonist 1 (Compound 4j) is identified as a 5-HT2A antagonist through in vitro calcium mobilization assays, with a pK_B of 8.1. It acts as an inverse agonist at the 5-HT7 receptor in functional assays (cAMP, pIC_50 = 7.0). The compound exhibits over 50-fold selectivity across 50 monoamine and peptide hormone receptors, ion channels, and neurotransmitter uptake sites. It shows in vitro affinity for h5-HT2B and 5-HT2C receptors, with pK_i values of 7.6 and 7.3, respectively. Binding to plasma proteins is below moderate level, with 30% fu in human plasma and 20% fu in rat plasma. The metabolic stability is high in both rat and human liver microsomes (t_1/2 > 60 minutes). At a concentration of 10 μM, there is no inhibition of cytochrome P450 enzymes, indicating a minimal likelihood of drug interactions.

The compound 5-HT7/5-HT2A receptor antagonist 1 demonstrates high oral bioavailability across various species: rat (100%), mouse, dog (98%), and monkey (72%). When administered orally in doses ranging from 0.03-1 mg/kg, this agent effectively acts as a potent central 5-HT7 receptor antagonist, capable of blocking 5-CT-induced hypothermia in rats. It also serves as a highly effective central 5-HT2A receptor antagonist, exhibiting high oral bioavailability and functional inhibitory effects within the central nervous system of mice at doses of 0.001-10 mg/kg, administered either orally or subcutaneously over 20 to 40 minutes. At oral doses of 0.01-10 mg/kg administered for one hour, it occupies the 5-HT2A receptor binding sites in the frontal cortex of rat brains, with an ED50 consistent with the central functional effects mediated by the rat 5-HT2A receptor (ED50 = 0.8 mg/kg). The compound shows only weak activity in inhibiting phenylephrine-induced pupil dilation in rats.