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Title: AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels

Abstract

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 dromotropicmore » 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.« less

Authors:
; ; ; ; ;  [1]
  1. (A. H. Robins Research Labs., Richmond, VA (USA))
Publication Date:
OSTI Identifier:
5644005
Resource Type:
Journal Article
Resource Relation:
Journal Name: Journal of Cardiovascular Pharmacology; (USA); Journal Volume: 17:1
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; CALCIUM; MEMBRANE TRANSPORT; PORINS; CHEMICAL COMPOSITION; SEROTONIN; RECEPTORS; BIOCHEMICAL REACTION KINETICS; BLOOD PLATELETS; BLOOD PRESSURE; CELL MEMBRANES; EDEMA; GUINEA PIGS; IN VITRO; IN VIVO; PIPERIDINES; RABBITS; RATS; TRACER TECHNIQUES; TRITIUM COMPOUNDS; ALKALINE EARTH METALS; AMINES; ANIMALS; AROMATICS; AUTONOMIC NERVOUS SYSTEM AGENTS; AZAARENES; AZINES; AZOLES; BIOLOGICAL MATERIALS; BLOOD; BLOOD CELLS; BODY FLUIDS; CELL CONSTITUENTS; DRUGS; ELEMENTS; HETEROCYCLIC COMPOUNDS; HYDROGEN COMPOUNDS; HYDROXY COMPOUNDS; INDOLES; ISOTOPE APPLICATIONS; KINETICS; MAMMALS; MATERIALS; MEMBRANE PROTEINS; MEMBRANES; METALS; NEUROREGULATORS; ORGANIC COMPOUNDS; ORGANIC NITROGEN COMPOUNDS; PATHOLOGICAL CHANGES; PROTEINS; PYRIDINES; PYRROLES; RADIOPROTECTIVE SUBSTANCES; REACTION KINETICS; RODENTS; SYMPATHOMIMETICS; SYMPTOMS; TRYPTAMINES; VERTEBRATES; 550201* - Biochemistry- Tracer Techniques

Citation Formats

Barrett, R.J., Appell, K.C., Kilpatrick, B.F., Proakis, A.G., Nolan, J.C., and Walsh, D.A.. AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels. United States: N. p., 1991. Web. doi:10.1097/00005344-199101000-00007.
Barrett, R.J., Appell, K.C., Kilpatrick, B.F., Proakis, A.G., Nolan, J.C., & Walsh, D.A.. AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels. United States. doi:10.1097/00005344-199101000-00007.
Barrett, R.J., Appell, K.C., Kilpatrick, B.F., Proakis, A.G., Nolan, J.C., and Walsh, D.A.. Tue . "AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels". United States. doi:10.1097/00005344-199101000-00007.
@article{osti_5644005,
title = {AHR-16303B, a novel antagonist of 5-HT2 receptors and voltage-sensitive calcium channels},
author = {Barrett, R.J. and Appell, K.C. and Kilpatrick, B.F. and Proakis, A.G. and Nolan, J.C. and Walsh, D.A.},
abstractNote = {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.},
doi = {10.1097/00005344-199101000-00007},
journal = {Journal of Cardiovascular Pharmacology; (USA)},
number = ,
volume = 17:1,
place = {United States},
year = {Tue Jan 01 00:00:00 EST 1991},
month = {Tue Jan 01 00:00:00 EST 1991}
}