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 action at 5-HT2 receptors and voltage-sensitive calcium channels. The 5-HT2 receptor-antagonistic properties of AHR-16303B were demonstrated by inhibition of (a) [3H]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) 5-HT-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) [3H]nimodipine binding to voltage-sensitive calcium channels on rabbit skeletal muscle membranes (IC50 = 15 nM), (b) KCl-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 radioligands to dopamine2 (DA2) alpha 1, alpha 2, H1, 5-HT1 alpha, beta 2, muscarinic M1, or sigma opioid receptors; had no effect on 5-HT3 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.
Barrett
R J
RJ
Department of Pharmacology, A. H. Robins Research Laboratories, Richmond, Virginia.
Appell
K C
KC
Kilpatrick
B F
BF
Proakis
A G
AG
Nolan
J C
JC
Walsh
D A
DA
D000818:Animals; D016275:Atrial Function; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism; D002122:Calcium Chloride / Q000494:pharmacology; D004231:Diuresis / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004487:Edema / Q000188:drug therapy; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007650:Ketanserin / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects; D009553:Nimodipine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011427:Propiophenones / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000378:metabolism; D011954:Receptors, Dopamine / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014316:Tritium; D014700:Verapamil / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D010880:Piperidines; D011427:Propiophenones; D011942:Receptors, Adrenergic, alpha; D011954:Receptors, Dopamine; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D014316:Tritium; C068453:AHR 16303B; D012701:Serotonin; D009553:Nimodipine; D007650:Ketanserin; D014700:Verapamil; D002122:Calcium Chloride; D002118:Calcium