AHR-16303B, a Novel Antagonist of 5-HT2 Receptors and Voltage-Sensitive Calcium Channels

In vivo and in vitro methods were used to characterize AHR-16303B, a novel compound with antagonistic actions at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [H] ketanserin binding to rat cerebral cortical membranes (Ic50 = 165 nM); (b) 5-hydroxytryptamine (5-HT)-induced foot edema in rats (minimum effective dose. (MED) = 0.32 mg/kg orally. p.o.)(c) 5-HT-induced vasopressor responses in spontaneously hypertensive rats (SHR) (ID50 = 0.18 mg/kg intravenously (i.v.). 1.8 mg/kg p.o.), (d) 5HT-induced antidiuresis in rats (MED = 1 mg/kg p.o.), and (e) platelet aggregation induced by 5-HT + ADP (IC50 = 1.5 mM). The calcium antagonist properties of AHR-16303B were demonstrated by inhibition of (a) [H] nimodipine binding to voltage-sensitve calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCI-stimulated calcium flux into cultured PC12 cells (IC50 = 81 nM), and (c) CaCl2-induced contractions of rabbit thoracic aortic strips (pA2 = 8.84). AHR-16303B had little or no effect on binding of radiligands to dopamine2 (DA2) α1. α2. H1. 5-HT1a. β2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT, receptor-mediated vagal bradycardia; and had only minor negative inotropic, chronotropic, and dromotropic effects on isolated guinea pig atria. In conscious SHR. 30 mg/kg p.o. AHR-16303B completely prevented the vasopressor responses to i.v. 5-HT, and decreased blood pressure (BP) by 24% 3 h after dosing.