B-HT 933 dihydrochloride

IC50: 0.44 μM

The contractile effects of adrenaline and noradrenaline may be mediated by both postjunctional α2- and α2-adrenoceptors on vascular smooth muscle. B-HT 933 is a selective α2-adrenoceptor agonist.

In vitro: B-HT 933, a selective α2-adrenoceptor agonist, contracts human subcutaneous resistance arteries by a mechanism largely dependent on the influx of extracellular Ca2+, probably through voltage-operated calcium channels. This action involves a pertussis toxin-sensitive G protein, possibly GQ [1].

In vivo: The dose-related effects of the selective α2-adrenoceptor agonist B-HT 933 on the body temperature of untreated and reserpine-treated mice were investigated. In untreated mice B-HT 933 induced a dose-related hypothermia. The highest dose of B-HT 933 elicited a marked hypothermia, whereas the maximal hypothermic effect of clonidine was less pronounced and reached a plateau at a dose of 0.5 mg/kg [2].

Clinical trial: Up to now, B-HT 933 is still in the preclinical development stage.

Reference:
[1] N. A. Parkinson & A.D. Hughes. The mechanism of action of 1c2-adrenoceptors in human isolated subcutaneous resistance arteries. British Journal of Pharmacology (1995) 115, 1463-1468
[2] D. J. Bill, I.E. Hughes & R.J. Stephens. The thermogenic actions of x2-adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic ac2-adrenoceptor mechanism. Br. J. Pharmacol. (1989), 96, 133-143

The mechanism of action of alpha 2-adrenoceptors in human isolated subcutaneous resistance arteries.[Pubmed:8564206]

Br J Pharmacol. 1995 Aug;115(8):1463-8.

1. The effect of noradrenaline and the selective alpha 2-adrenoceptor agonist, azepexole, on tone and intracellular Ca2+ ([Ca2+]i) was examined in human isolated subcutaneous resistance arteries. Isolated arteries were mounted on an isometric myograph and loaded with the Ca2+ indicator, fura-2, for simultaneous measurement of force and [Ca2+]i. 2. High potassium solution (KPSS), noradrenaline and azepexole increased [Ca2+]i and contracted subcutaneous arteries in physiological saline. When extracellular Ca2+ was removed and the calcium chelator, BAPTA, added to the physiological saline (PSSo), responses to noradrenaline were transient and reduced, and responses to azepexole were markedly inhibited. 3. Ryanodine, an agent which interferes with Ca2+ release from intracellular stores, had little effect on contractile responses to KPSS, noradrenaline or azepexole in physiological saline. The response to caffeine in physiological saline was inhibited by ryanodine. In PSSo, ryanodine partially inhibited contractile responses to noradrenaline and azepexole, and completely abolished the response to caffeine. 4. Noradrenaline and azepexole both significantly increased maximum force achieved by cumulative addition of Ca2+ to a Ca(2+)-free depolarizing solution and shifted the calculated relationship between [Ca2+]i and force to the left, suggesting these agents increase the sensitivity of the contractile apparatus to [Ca2+]i. 5. (-)-202 791, a dihydropyridine antagonist of voltage-operated calcium channels partially inhibited both the contractile response and the rise in [Ca2+]i induced by azepexole. Pre-treatment of arteries with pertussis toxin inhibited responses to azepexole, but had no significant effect on tone induced by KPSS or noradrenaline. ETYA, an inhibitor of phospholipase A2, lipoxygenase and cyclo-oxygenase, had no effect on azepexole-induced contraction in the presence of N omega nitro-L-arginine methyl ester.6. Azepexole, a selective alpha2-adrenoceptor agonist, contracts human subcutaneous resistance arteries by a mechanism largely dependent on the influx of extracellular Ca2", probably through voltage-operated calcium channels. This action involves a pertussis toxin-sensitive G protein, possibly Gi.

The thermogenic actions of alpha 2-adrenoceptor agonists in reserpinized mice are mediated via a central postsynaptic alpha 2-adrenoceptor mechanism.[Pubmed:2564288]

Br J Pharmacol. 1989 Jan;96(1):133-43.

1. The dose-related effects of the selective alpha 2-adrenoceptor agonists clonidine, UK-14,304 and B-HT 933 on the body temperature of untreated and reserpine-treated mice were investigated. 2. In untreated mice all three agonists induced a dose-related hypothermia. The highest doses of UK-14,304 and B-HT 933, 3 and 100 mg kg-1 respectively, elicited a marked (10 degrees C) hypothermia, whereas the maximal hypothermic effect of clonidine (5.5 degrees C) was less pronounced and reached a plateau at a dose of 0.5 mg kg-1 i.p. 3. Reserpine (2.5 mg kg-1, s.c.) induced a marked hypothermia in the mouse; 18 h after injection body temperature had decreased to only slightly (0.5-1.5 degrees C) above ambient (19 degrees C). 4. All three alpha 2-agonists produced a partial dose-related reversal of reserpine-induced hypothermia; maximal thermogenic responses (9-10 degrees C increases in body temperature) were elicited by doses of 0.2, 0.5 and 16 mg kg-1 i.p. of clonidine, UK-14,304 and B-HT 933 respectively, and the log dose-response curves for all 3 agonists were bell-shaped. 5. Following intracerebroventricular administration to reserpine-treated mice, the thermogenic response to clonidine was more rapid in onset, and the agonist was 20 fold more potent than when injected i.p. 6. The selective alpha 2-adrenoceptor antagonists, idazoxan (0.05-0.5 mg kg-1), Wy 26392 (0.3-5.0 mg kg-1) and yohimbine (0.1-1.6 mg kg-1) given orally attenuated the thermogenic responses to all 3 agonists in reserpinized mice in a dose-related manner. Pretreatment with a single dose of idazoxan (0.3 mg kg-1, orally) elicited a 6 fold parallel shift to the right in the dose-response curve to clonidine. 7. The selective alpha 1-adrenoceptor antagonists, prazosin (10 mg kg-1) and indoramin (3-10 mg kg-1), and the beta-adrenoceptor antagonist, propranolol (10 mg kg-1), only partially attenuated the thermogenic responses to the alpha 2-agonists in reserpinized mice. These effects were variable and not clearly dose-related. 8. Pretreatment of reserpinized mice with the catecholamine synthesis inhibitor, alpha-methyl-p-tyrosine, markedly attenuated (60-95%) the thermogenic response to the noradrenaline uptake inhibitor, desipramine (0.13-12.5 mg kg-1, i.p.), but only slightly reduced (10-35%) that to clonidine (0.032-0.5 mg kg-1, i.p.). 9. These results suggest that alpha2-adrenoceptor agonists reverse reserpine-induced hypothermia via a central mechanism involving activation of postsynaptic alpha 2-adrenoceptors.