Histamine H3 receptor ( IC50 = 1.9 μM )

Betahistine mesylate (0-10 μM) inhibits [¹²⁵I]iodoproxyfan binding to the membranes of CHO (rH₃₍₄₄₅₎R) and CHO (hH3(445)R) cells with IC50 values of 1.9 μM and 3.3 μM, respectively. Lead to K_i values of 1.4 μM and 2.5 μM, respectively[2].
Betahistine mesylate (0-10 μM) regulates the formation of cAMP in CHO (rH₃₍₄₄₅₎R), CHO (rH₃₍₄₁₃₎R), and CHO (hH3(445)R) cells. Betahistine mesylate exhibits apparent inverse agonistic behavior at low concentrations, gradually increasing the formation of cAMP with EC50 values of 0.1 nM, 0.05 nM, and 0.3 nM, respectively. On the other hand, betahistine mesylate, at concentrations greater than 10 nM, inhibits full agonist activity and the formation of cAMP in CHO (rH₃₍₄₄₅₎R) with an EC50 value of 0.1 μM[2].

Betahistine mesylate (intraperitoneal or oral administration; 0.1-30 mg/kg; single dose) increased tele-methylhistamine (t-MeHA) levels with an ED50 of 0.4 mg/kg after acute administration, suggesting the opposite agonism. Furthermore, in male Swissmice, it raises t-MeHA levels with an ED50 of 2 mg/kg following acute oral administration[2].
Betahistine mesylate (oral adminstration; 1 and 5 mg/kg; daily for 3 weeks) decreases the amount of pro-inflammatory cytoK_ines and lessens the severity of arthritis in the paw tissues of CIA mice[3].

Researchers previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H(3) receptors (H(3)Rs). However, H(3)Rs exhibit constitutive activity, and most H(3)R antagonists act as inverse agonists. Here, Researchers have investigated the effects of betahistine at recombinant H(3)R isoforms. On inhibition of cAMP formation and [(3)H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H(3)Rs [2].

In vitro, betahistine suppressed CD4(+) T cell differentiation into Th17 cells. These results indicate that betahistine is effective in suppressing both inflammatory and Th17 responses in mouse CIA and that it may have therapeutic value as an adjunct treatment for rheumatoid arthritis [3].

Collagen-induced arthritis (CIA) DBA/1 male mouse model
1 mg/kg; 5mg/kg
Oral adminstration; day 21 to day 42 after a 21-day CIA induction

---

Histamine antagonism has been implicated in antipsychotic drug-induced weight gain. Betahistine, a histamine enhancer with H1 agonistic/H3 antagonistic properties (48 mg t.i.d.), was coadministered with olanzapine (10 mg/day) in three first-episode schizophrenia patients for 6 weeks. Body weight was measured at baseline and weekly thereafter. Clinical rating scales were completed at baseline and at week 6. All participants gained weight (mean weight gain 3.1+/-0.9 kg) and a similar pattern of weight gain was observed: an increase during the first 2 weeks and no additional weight gain (two patients) or minor weight loss (one patient) from weeks 3 to 6. None gained 7% of baseline weight, which is the cut-off for clinically significant weight gain. Betahistine was safe and well tolerated and did not interfere with the antipsychotic effect of olanzapine. Our findings justify a placebo-controlled evaluation of the putative weight-attenuating effect of betahistine in olanzapine-induced weight gain.[1]

---

The inverse agonist potency of betahistine and its affinity on [(125)I]iodoproxyfan binding were similar in rat and human. We then investigated the effects of betahistine on histamine neuron activity by measuring tele-methylhistamine (t-MeHA) levels in the brains of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED(50) of 0.4 mg/kg, indicating inverse agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED(50) of 2 mg/kg, a rightward shift probably caused by almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H(3) autoreceptors.[2]

---

The objective of this study was to evaluate the potential therapeutic effects of betahistine dihydrochloride (betahistine) in a collagen-induced arthritis (CIA) mouse model. CIA was induced in DBA/1 male mice by primary immunization with 100μl of emulsion containing 2mg/ml chicken type II collagen (CII) mixed with complete Freund's adjuvant (CFA) in an 1:1 ratio, and booster immunization with 100μl of emulsion containing 2mg/ml CII mixed with incomplete Freund's adjuvant (IFA) in an 1:1 ratio. Immunization was performed subcutaneously at the base of the tail. After being boosted on day 21, betahistine (1 and 5mg/kg) was orally administered daily for 2weeks. The severity of CIA was determined by arthritic scores and assessment of histopathological joint destruction. Expression of cytokines in the paw and anti-CII antibodies in the serum was evaluated by ELISA. The proliferative response against CII in the lymph node cells was measured by (3)H-thymidine incorporation assay. The frequencies of different CII specific CD4(+) T cell subsets in the lymph node were determined by flow-cytometric analysis. Betahistine treatment attenuated the severity of arthritis and reduced the levels of pro-inflammatory cytokines, including TNF-α, IL-6, IL-23 and IL-17A, in the paw tissues of CIA mice. Lymph node cells from betahistine-treated mice showed a decrease in proliferation, as well as a lower frequency of Th17 cells. [3]

Absorption, Distribution and Excretion
After oral administration, betahistine is rapidly and almost completely absorbed from the gastrointestinal tract. Peak plasma concentration (Cmax) is reached within 1 hour on an empty stomach; Cmax is delayed after eating, but the total absorption is similar. Therefore, food has little effect on the absorption of betahistine. [A220563,16388]
Betahistine is primarily excreted in the urine; approximately 85-91% of the drug is detectable in urine samples within 24 hours after administration.
In rat pharmacokinetic studies, betahistine was found to be distributed systemically. There is currently no data on the volume of distribution of betahistine in humans. Metabolism/Metabolites
Betahistine is primarily metabolized to the inactive metabolite 2-pyridineacetic acid. Clinical and in vitro studies have provided evidence that monoamine oxidase is responsible for the metabolism of betahistine.

---

Biological half-life
The half-life of betahistine is 3-4 hours.

Protein Binding

It has been reported that the plasma protein binding rate of betahistine is less than 5%.

---

Oral LD50 in rats: 6110 mg/kg, Pharmaceutical Issues, 13(63), 1985
Intraperitoneal LD50 in rats: 980 mg/kg, Pharmaceutical Issues, 13(63), 1985
Oral LD50 in mice: 2920 mg/kg, Pharmaceutical Issues, 13(63), 1985
Intraperitoneal LD50 in mice: 320 mg/kg, Pharmaceutical Issues, 13(63), 1985

[1]. The effect of Betahistine mesylate, a histamine H1 receptor agonist/H3 antagonist, on olanzapine-induced weight gain in first-episode schizophrenia patients. Int Clin Psychopharmacol. 2005 Mar;20(2):101-3.

[2]. Effects of Betahistine mesylate at histamine H3 receptors: mixed inverse agonism/agonism in vitro and partial inverse agonism in vivo.J Pharmacol Exp Ther. 2010 Sep 1;334(3):945-54.

[3]. Betahistine mesylate attenuates murine collagen-induced arthritis by suppressing both inflammatory and Th17 cell responses.Int Immunopharmacol. 2016 Oct;39:236-245.

Betahistine mesylate is an arylalkylamine drug. It is a histamine analog and H1 receptor agonist with vasodilatory effects. It is used to treat Meniere's disease and vascular headaches, but may worsen bronchial asthma and peptic ulcers. Betahistine hydrochloride is the hydrochloride form of betahistine, a histamine analog with weak histamine H1 receptor agonist activity and strong histamine H3 receptor antagonist activity. After intranasal administration, betahistine binds to histamine H1 and H3 receptors, exerting its agonist and antagonist effects locally and centrally. This can promote blood flow to the cochlea, vestibule, and brain, reduce neuronal firing in the vestibular nuclei, and increase the synthesis and release of histamine in the brain, thereby promoting vestibular compensation. Increased blood flow around the inner ear can reduce the amount of fluid in the inner ear, thus relieving dizziness, tinnitus, and hearing loss. It is a histamine analog and H1 receptor agonist with vasodilatory effects. It is used to treat Meniere's disease and vascular headaches, but may worsen bronchial asthma and peptic ulcers.

C₁₀H₂₀N₂O₆S₂

328.41

328.076

C, 36.57; H, 6.14; N, 8.53; O, 29.23; S, 19.53

54856-23-4

Betahistine; 5638-76-6; Betahistine dihydrochloride; 5579-84-0; Betahistine-d3 dihydrochloride; 244094-72-2; Betahistine mesylate; 54856-23-4; Betahistine-13C,d3 dihydrochloride; 5638-76-6; 54856-23-4 (mesylate)

198334

White to off-white solid powder

210.9ºC at 760 mmHg

112°C

96.7ºC

2.404

3

8

3

20

176

0

S(C([H])([H])[H])(=O)(=O)O[H].N([H])(C([H])([H])[H])C([H])([H])C([H])([H])C1=C([H])C([H])=C([H])C([H])=N1

ZBJJDYGJCNTNTH-UHFFFAOYSA-N

InChI=1S/C8H12N2.2CH4O3S/c1-9-7-5-8-4-2-3-6-10-8;2*1-5(2,3)4/h2-4,6,9H,5,7H2,1H3;2*1H3,(H,2,3,4)

methanesulfonic acid;N-methyl-2-pyridin-2-ylethanamine

PT9; PT-9; BRN0112294; BRN-0112294; Betahistine mesylate; 54856-23-4; Betahistine mesilate; Meginalisk; Merislon; Riptonin; Betahistine Methanesulfonate; betahistine dimesylate; BRN 0112294; beta-Histine; Betahistine; NSC 42617; PT 9 base; Serc base

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: (1). This product requires protection from light (avoid light exposure) during transportation and storage.  (2). Please store this product in a sealed and protected environment (e.g. under nitrogen), avoid exposure to moisture.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO: 65~100 mg/mL (197.9~304.5 mM))

Solubility in Formulation 1: ≥ 2.5 mg/mL (7.61 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

Solubility in Formulation 2: ≥ 2.5 mg/mL (7.61 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

---

View More

Solubility in Formulation 3: ≥ 2.5 mg/mL (7.61 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

 (Please use freshly prepared in vivo formulations for optimal results.)