α₂‐adrenoceptor antagonist properties of OPC‐28326, a novel selective peripheral vasodilator

Abstract

1 Antagonistic properties of OPC-28326 ([4-(N-methyl-2-phenylethylamino)-1-(3,5-dimethyl-4-propionyl-aminobenzoyl)] piperidine hydrochloride monohydrate), a selective peripheral vasodilator, were investigated by analysing the data from functional studies in various tissues from the rat and binding studies of the drug to a 2 -adrenoceptor subtypes. 2 Using a human recombinant receptor and rat kidney cortex, we found that OPC-28326 displays a nities to a 2A -, a 2B -and a 2C -adrenoceptors with K i values of 2040, 285, and 55 nM, respectively. The K i values of yohimbine for a 2A -, a 2B -, and a 2C -adrenoceptors were 3.0, 2.0 and 11.0 nM, respectively. 3 B-HT 920, an a 2 -adrenoceptor agonist, produced a pressor response via peripheral postsynaptic a 2 -adrenoceptor stimulation (thought to be an a 2B -subtype) in a reserpine-pretreated pithed rat preparation. OPC-28326 (3 ± 30 mg kg 71 , i.v.) and yohimbine (0.3 ± 3 mg kg 71 , i.v.) caused dosedependent rightward shift in the pressor dose-response curve induced by B-HT 920. The apparent pA 2 values were 1.55 (0.87 ± 2.75, 95% con®dence interval) and 0.11 (0.06 ± 0.21) mg kg 71 , respectively. The potency of OPC-28326 was about 14 times less than that of yohimbine. 4 Clonidine inhibited the tension developed by electrical stimulation, of the rat vas deferens, by its peripheral presynaptic a 2A/D -adrenoceptor action. OPC-28326 (1 ± 100 mM) and yohimbine (10 ± 1000 nM) caused a rightward shift in the concentration-response curve of clonidine. The pA 2 values were 5.73 (5.54 ± 5.91) and 7.92 (7.84 ± 8.01), respectively, providing evidence for a potency of OPC-28326 of about 155 times less than that of yohimbine. 5 Mydriasis was induced by brimonidine via stimulation of central a 2A/D -adrenoceptors in anaesthetized rats. Intravenous OPC-28326 had no e ect on this action, even at a very high dose of 10 mg kg 71 i.v., while yohimbine (0.1 ± 0.3 mg kg 71 i.v.) inhibited mydriasis in a dose-dependent manner, indicating that OPC-28326 was at least 100 times less potent than yohimbine in regard to the anti-mydriatic e ect. 6 These data suggest that OPC-28326 preferentially exerts peripheral and postsynaptic antagonistic actions on the a 2B -and a 2C -adrenoceptor subtypes.

Efficacy and tolerability of a selective α2C‐adrenergic receptor blocker in recovery from cold‐induced vasospasm in scleroderma patients: A single‐center, double‐blind, placebo‐controlled, randomized crossover study

“…OPC‐28326 (4‐[N‐methyl‐2‐phenylethyl‐amino]‐1‐[3,5‐dimethyl‐4‐propionyl‐aminobenzoyl] piperidine hydrochloride monohydrate), a piperidine derivative, is a selective α‐adrenergic antagonist with preferential binding to the α 2C ‐AR subtype (α 2C is several‐fold stronger than α 2B , followed in decreasing strength by α 2A and α 1 ) (4–6). Animal studies involving OPC‐28326 have demonstrated improved hind‐limb blood flow during cold exposure and normalized skin temperature under anesthesia with this drug (6, 7).…”

Method for Simultaneous Recording of the Prostatic Contractile and Urethral Pressure Responses in Anesthetized Rats and the Effects of Tamsulosin

“…Our present findings indicated the possibility that prejunctional a1-adrenoceptors modulated the release of norepinephrine from sympathetic nerve terminals in rat urethra. It is accepted that prejunctional a 2 -adrenoceptors modulate the release of norepinephrine from sympathetic nerve terminals, and clonidine has been used to study this effect (18). To investigate the presence of prejunctional a 2-adrenoceptors, we also examined the effect of clonidine on the urethral pressure response to ES of the HGNs.…”

Effect of Oral OPC-28326, a Selective Femoral Arterial Vasodilator, on Hindlimb Subcutaneous Tissue Temperature in Conscious Dogs Under Buprenorphine Sedation

“…We also suggested that properties of the a2-adrenoceptor antagonistic action of OPC-28326 showed high selectivity for postsynapses compared to yohimbine, and OPC-28326 did not affect the central nervous action induced by an a2-adrenoceptor agonist (2). OPC-28326 showed affinities for a2A-, a2B-and a2C-adrenoceptors with Ki values of 2040, 285 and 55 nM, respectively, in receptor binding studies (2). It was reported that cooling augmented vasoconstriction induced by a2-adrenoceoptor activation and that postjunctional a2-adrenoceptors are important for thermoregulation in this vascular bed (8,9).…”

“…This drug has little effect on other cardiovascular parameters, such as blood pressure, heart rate, contractile force of myocardium, and blood flow in other areas, such as the carotid, vertebral, coronary, renal and mesentery arteries (1). a 2 -Adrenoceptor blocking action of OPC-28326 may be involved its selective vasodilator action on the femoral artery (2). To evaluate the effects of oral administration of OPC-28326, we measured subcutaneous temperature using a wire-type thermometer in conscious dogs sedated with buprenorphine.…”