B-HT 920

B-HT 920, marketed as talipexole in Japan, is a full agonist at both pre- and postsynaptic D-2 dopamine receptors agonist and α2-adrenergic receptor agonist. In addition, it is a 5-HT3 receptor antagonist in both rat cortical and intestinal membrane fractions with Ki values of 0.35 μM and 0.22 μM, respectively. [1, 2]
Adrenergic receptor and dopamine receptors are distributed in many cells. α-adrenergic receptor can be divided into two categories, α1 and α2 adrenergic receptors, which involve in functions of smooth muscles and veins. Dopamine receptors are widely distributed in the brain and control neural signaling that modulates many important behaviors
By measuring the DOPA in mice corpus striatum, effect of B-HT 920 on the presynaptic D-2 receptors was studied in mice treated with gamma-butyrolactone (GBL, 750 mg/kg i.p.). B-HT 920 inhibited the synthesis of DA to approximately the same extent from 0.1 to 3mg/kg. Haloperidol (2 mg/kg) completely inhibited the effects of 0.1 to 1 mg/kg B-HT 920. Furthermore, B-HT 920 on postsynaptic DA receptors were studied in mice in which the DA stores had been depleted by reserpine. The motor activity of three groups of mice was recorded by the use of electronic motility meters. The motor activity was enhanced by apomorphine. Combined treatment with B-HT920 (0.1 mg/kg) and SKF38393 produced an even greater increase in the motor activity of the reserpine-treated mice. Moreover, B-HT 920 at a dose 1 mg/ kg had a persistent effect on mice. A study was performed relating the involvement of α-adrenergic receptors in the cardiovascular responses to intracerebroventricular (ICV) injection of B-HT 920. In sham-operated rats, B-HT 920 (10–60 mg) caused cardiovascular activities including increased blood pressure and bradycardia. However, in sinoaortic-denervated rats, after the pressor response, there was a decline in blood pressure observed. The responses to this agent were greater in sinoaortic-denervated rats than in sham-operated subjects. B-HT 920 was assessed in combination of other active agents. Treatment with the α2-adrenergic receptor antagonist yohimbine (30 mg), the imidazoline receptor antagonist idazoxan (15 mg) and the α1A -adrenergic receptor antagonist 5-methylurapidil (15 mg) blocked the revesed effects of B-HT 920 (30 mg). The α1-adrenergic receptor antagonist prazosin (15mg) and the α1B -adrenergic receptor antagonist chloroethylclonidine (100 mg) did not alter the responses to B-HT 920. [1, 3]
References:
[1] Andén, N-E., and M. Grabowska-Andén. "B-HT 920 is a full agonist at both pre-and postsynaptic D-2 dopamine receptors." Journal of Neural Transmission/General Section JNT 79.3 (1990): 209-214.
[2] Nishio, Hiroaki, et al. "5-HT 3 receptor blocking properties of the antiparkinsonian agent, talipexole." General Pharmacology: The Vascular System 27.5 (1996): 779-785.
[3] Ricci, Daniel, and Carlos Alberto Taira. "Adrenoceptor involvement in the cardiovascular responses to B-HT 920 in sinoaortic denervated rats." General Pharmacology: The Vascular System 32.1 (1999): 29-34.

Dopamine receptor mediated antidepressant action of B-HT 920 in mice.[Pubmed:8070836]

Indian J Exp Biol. 1994 Mar;32(3):172-5.

Possible involvement of dopaminergic (DAergic) system in forced swimming-induced immobility (despair behaviour) was investigated in mice. B-HT 920 (0.05 and 0.1 mg/kg), a post-synaptic DAergic agonist, produced a dose dependent reduction in immobility period, which was sensitive to blockade by haloperidol (0.5 mg/kg) and sulpiride (100 mg/kg). This effect was also blocked by alpha 2 antagonist yohimbine (5 mg/kg). SKF 38393 (5 mg/kg), a D1-DA agonist potentiated the action of B-HT 920. Reserpinization (2 mg/kg, 24 hr prior) produced despair immobility in mice. When a low dose of B-HT 920 (0.05 mg/kg) was given to reserpinized animals, the duration of immobility period was further increased. But on the other hand, a higher dose (0.1 mg/kg) of it reduced reserpine-induced immobility. Desipramine (5 and 10 mg/kg), elicited a dose dependent reduction in the immobility period, which was sensitive to blockade by sulpiride (100 mg/kg). Desipramine (10 mg/kg) showed a diphasic response in combination with B-HT 920, i.e., a potentiation of the response due to a low dose of B-HT 920 (0.05 mg/kg) and an antagonism of the response due to a higher dose of B-HT 920 (0.1 mg/kg), respectively. SKF 38393 (5 mg/kg), potentiated the action of desipramine (5 mg/kg). SKF 38393 (5 mg/kg) further potentiated the action of desipramine (5 mg/kg) and B-HT 920 (0.05 mg/kg). These observations suggests that B-HT 920 reduces behavioural immobility by DAergic mechanism and desipramine also modulates D2-DA receptors in its anti-depressant action.

Hypotensive and bradycardic effects of talipexole (B-HT 920) in anaesthetized rabbits are antagonized by metoclopramide but not by yohimbine.[Pubmed:8104317]

Naunyn Schmiedebergs Arch Pharmacol. 1993 Jul;348(1):58-64.

The interactions of talipexole (B-HT 920) and clonidine with selective alpha-adrenoceptor antagonists, yohimbine (alpha 2) and prazosin (alpha 1), as well as with dopamine receptor antagonists, metoclopramide (D2), domperidone (D2) and SCH23,390 (D1) were investigated in anaesthetized rabbits after i.v. administration. Both talipexole (0.03-0.1 mg/kg) and clonidine (0.01-0.03 mg/kg) dose-dependently induced hypotension and bradycardia. Talipexole had a shorter duration of action. The hypotensive effect of the alpha 2-adrenoceptor and D2 agonist talipexole (0.03 mg/kg) was antagonized by pretreatment with metoclopramide (3 mg/kg) or domperidone (0.3-3 mg/kg), but not with yohimbine (3 mg/kg), prazosin (0.1 mg/kg) or SCH23,390 (1 mg/kg). Its bradycardic effect was antagonized only by metoclopramide (3 mg/kg). The hypotensive and bradycardic effects of clonidine (0.03 mg/kg) were most effectively antagonized by yohimbine (0.3-3 mg/kg). These findings indicate that in anaesthetized rabbits after i.v. administration, talipexole may lower blood pressure by peripheral, and heart rate by central, dopamine D2 agonism.

Adrenoceptor involvement in the cardiovascular responses to B-HT 920 in sinoaortic denervated rats.[Pubmed:9888250]

Gen Pharmacol. 1999 Jan;32(1):29-34.

1. A study was made relating the involvement of alpha-adrenoceptors in the cardiovascular responses to intracerebroventricular (i.c.v.) injection of B-HT 920, a clonidine-type drug, in conscious sham-operated and sinoaortic-denervated rats. 2. Wistar rats were used, 7 days after the sham operation or sinoaortic denervation. For i.c.v. injection of drugs, a guide cannula had been previously implanted in the left lateral ventricle. 3. In sham-operated rats, cardiovascular responses to B-HT 920 (10-60 microg) were increased blood pressure and bradycardia; but, in sinoaortic-denervated rats, after the pressor response, a decrease in blood pressure also was seen. The responses to this agent were greater in sinoaortic-denervated rats than in sham-operated animals. Treatment with the alpha2-adrenoceptor antagonist yohimbine (30 microg), the imidazoline receptor antagonist idazoxan (15 microg) and the alpha1A-adrenoceptor antagonist 5-methylurapidil (15 microg) blocked the responses to B-HT 920 (30 microg). The alpha1-adrenoceptor antagonist prazosin (15 microg) and the alpha1B-adrenoceptor antagonist chloroethylclonidine (100 microg) did not modify the responses to agonist. 4. Sinoaortic denervation enhances the cardiovascular responses to B-HT 920. Moreover, the effects of i.c.v. administration of B-HT 920 could be mediated by several types of brain receptors: imidazoline receptors and alpha1A- and alpha2-adrenoceptors.

The effect of B-HT 920, a dopamine D2 agonist, on bar-press feeding in the monkey.[Pubmed:7914026]

Physiol Behav. 1994 Jun;55(6):1125-30.

Although the dopamine (DA) system has been shown to regulate food intake, the function of the DA receptor subtypes on behavior still remains to be elucidated. In the present study, we examined the effect of B-HT 920, a selective agonist of DA D2 receptors that preferentially affect presynaptic autoreceptors, on both food consumption and execution of a high fixed-ratio bar-press task for food reward in monkeys. Two kinds of bar-press task were used: 1) a cue-triggered bar-press task during the first 40 trials, and 2) a self-paced bar-press task in which the monkeys freely performed bar-press trials until they were satiated. A SC injection of B-HT 920 (25 micrograms/kg) increased food consumption in the home cage. The same facilitatory effect on food consumption was also observed in the operant task condition. During the cue-triggered bar-press task, however, both the latency of the bar-press responses to a cue light and the time required to complete the bar-press trials were prolonged after the injection of B-HT 920. The results suggest that the activation of D2 autoreceptors suppresses the operant food acquisition behavior and increases food consumption through an inhibition of the satiety mechanism rather than an activation of any hunger-related drive.

A functional fast scan cyclic voltammetry assay to characterize dopamine D2 and D3 autoreceptors in the mouse striatum.[Pubmed:20567609]

ACS Chem Neurosci. 2010 Mar 12;1(6):450-462.

Dopamine D2 and D3 autoreceptors are located on pre-synaptic terminals and are known to control the release and synthesis of dopamine. Dopamine D3 receptors have a fairly restricted pattern of expression in the mammalian brain. Their localization in the nucleus accumbens core and shell is of particular interest because of their association with the rewarding properties of drugs of abuse. Using background subtracted fast scan cyclic voltammetry, we investigated the effects of dopamine D2 and D3 agonists on electrically stimulated dopamine release and uptake rates in the mouse caudate-putamen and nucleus accumbens core and shell. The dopamine D2 agonists (-)-quinpirole hydrochloride and 5,6,7,8-Tetrahydro-6-(2-propen-1-yl)-4H-thiazolo[4,5-d]azepin-2-amine dihydrochloride (B-HT 920) had the same dopamine release inhibition effects on caudate-putamen and nucleus accumbens (core and shell) based on their EC(50) and efficacies. This suggests that the dopamine D2 autoreceptor functionality is comparable in all three striatal regions investigated. The dopamine D3 agonists (4aR,10bR)-3,4a,4,10b-Tetrahydro-4-propyl-2H,5H-[1]benzopyrano-[4,3-b]-1,4-oxazin -9-ol hydrochloride ((+)-PD 128907) and (+/-)-7-Hydroxy-2-dipropylaminotetralin hydrobromide (7-OH-DPAT) had a significantly greater effect on dopamine release inhibition in the nucleus accumbens shell than in caudate-putamen. This study confirms that, the dopamine D3 autoreceptor functionality is greater in the nucleus accumbens shell followed by the nucleus accumbens core, with the caudate-putamen having the least. Neither dopamine D2 nor D3 agonists affected the uptake rates in nucleus accumbens but concentrations greater than 0.3 muM lowered the uptake rate in caudate-putamen. To validate our method of evaluating dopamine D2 and D3 autoreceptors, sulpiride (D2 antagonist) and nafadotride (D3 antagonist) were used to reverse the effects of the dopamine agonists to approximately 100% of the pre-agonist dopamine release concentration. Finally, these results demonstrate a functional voltammetric assay that characterizes dopamine D2-like agonist as either D2- or D3-preferring agonists by taking advantage of the unique receptor density within the striatum.

5-HT3 receptor blocking properties of the antiparkinsonian agent, talipexole.[Pubmed:8842679]

Gen Pharmacol. 1996 Jul;27(5):779-85.

1. Talipexole showed moderate displacement activity of 3H-GR 65630 binding to 5-HT3 receptors in both rat cortical and intestinal membrane fractions with Ki values of 0.35 microM and 0.22 microM, respectively. 2. Bromocriptine failed to displace the binding activity in either experimental system even at a concentration of 10 microM. 3. Both talipexole and tropisetron were found to significantly inhibit 5-HT3 receptor-mediated effects of 5-HT in isolated guinea-pig ileum or atrium; however, the effect of talipexole was weaker than that of tropisetron. 4. Bromocriptine, in contrast, had no antagonistic effects on 5-HT3 receptor-mediated activity in guinea-pig ileum or atrium. 5. It was concluded that talipexole might act as an antagonist on 5-HT3 receptors in both brain and intestinal tissues.

In vivo comparisons of the effects of quinpirole and the putative presynaptic dopaminergic agonists B-HT 920 and SND 919 on striatal dopamine and acetylcholine release.[Pubmed:8095550]

J Pharmacol Exp Ther. 1993 Mar;264(3):1344-51.

The extent to which the putative dopamine (DA) autoreceptor agonists B-HT 920 (6-allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo[4,5d]azepine dihydrochloride) and SND 919 (2-amino-4,5,6,7-tetrahydro-6-propylamino- benzthiazol dihydrochloride) and the potent D2 receptor agonist quinpirole have differential effects on pre- and postsynaptic DA receptors was determined by using in vivo microdialysis to monitor the effects of these compounds on extracellular concentrations of DA and acetylcholine (ACh) in the striata of freely moving rats. B-HT 920 and SND 919 reduced interstitial concentrations of DA, but not ACh, when administered s.c. at doses of 0.05 and 0.1 mg/kg. Quinpirole (0.05 and 0.2 mg/kg) decreased extracellular concentrations of both DA and ACh. Hence, relative to its effects on DA, quinpirole was more potent than the other drugs at DA receptors controlling ACh release. These results are consistent with the hypothesis that B-HT 920 and SND 919 have preferential actions on DA autoreceptors. Local application of the selective D2 receptor antagonist raclopride produced similar dose-dependent increases in DA and ACh release. It is unlikely therefore that differences in the degree to which endogenous DA inhibits transmitter release from nigrostriatal terminals and cholinergic neurons can account for the greater sensitivity of the former to the depressant actions of systemically administered B-HT 920 and SND 919. As was the case with systemic administration, local striatal application of B-HT 920 produced larger decreases in extracellular DA than ACh.(ABSTRACT TRUNCATED AT 250 WORDS)

Talipexole dihydrochloride (B-HT 920 dihydrochloride) is a dopamine D2 receptor agonist, α2-adrenoceptor agonist and 5-HT3 receptor antagonist, which displays antiParkinsonian activity.

B-HT 920,36085-73-1,Talipexole; Talipexole dihydrochloride;,Natural Products,5-HT Receptor, buy B-HT 920 , B-HT 920 supplier , purchase B-HT 920 , B-HT 920 cost , B-HT 920 manufacturer , order B-HT 920 , high purity B-HT 920