In CHO cells, bromocriptine increases the expression of D2 dopamine receptors, which then bind to [35S]-GTPγS with a pEC50 of 8.15±0.05[1]. Another potent inhibitor of brain nitric oxide synthase is bromocriptine. It was shown that the ergot alkaloid bromocriptine (BKT) had weak effect against inducible macrophage NOS (IC50>100 μM), but it was a potent inhibitor of pure neuronal nitric oxide synthase (NOS) (IC50=10±2 μM) [2]. It has been discovered that at least one human cytochrome P450 enzyme is inhibited by bromocriptine. Strong CYP3A4 inhibitor bromocriptine has an interaction IC50 value of 1.69 μM [3].

When compared to the control group, the group administered with 2 mg/kg intraperitoneal injections of bromocriptine, a dopamine agonist, demonstrated a noteworthy anti-immobility effect. When bromocriptine was given 30 minutes after the last dose of the 7-day MPE therapy and an FST was conducted, the anti-immobility effects of this dopaminergic agonist on MPE (200 mg/kg, orally) were shown to be significantly and dose-dependently enhanced when compared with MPE treatment alone. When compared to the control group, the group treated with 2 mg/kg of the dopamine agonist bromocriptine intraperitoneally (i.p.) exhibited a substantial decrease in immobility time. When bromocriptine (100 and 200 mg/kg, po) was administered following 7 days of pretreatment with MPE, the anti-immobility effect of MPE was significantly and dose-dependently enhanced when compared to MPE treatment alone [4]. When bromocriptine was administered intraperitoneally, the CCI-IoN group saw a significant, dose-dependent (0.1 mg and 1 mg/Kg) reduction in pain scores when compared to the sham group. This effect persisted for six hours. Scores decreased most when the highest dose was applied (P<0.01). The DR1 agonist SKF8129 was employed as a positive control. Comparing intraperitoneal delivery to sham surgery (saline injection), there was a nonsignificant rise in SMA scores. When bromocriptine was administered intracervically, the SMA scores were much lower than when saline injection was used as a sham procedure. Bromocriptine has a 20-minute half-life. as bromocriptine was administered intraperitoneally, the SMA scores of the CCI-IoN α + α 6-OHDA damage group significantly decreased in a dose-dependent manner as compared to the sham group. Six hours pass during its impact. Administration of SKF81297 resulted in higher allodynia scores. When compared to sham surgery (rats injected with normal saline), intraacisternal infusion of bromocriptine dramatically reduced SMA scores, and its effects lasted for 30 minutes [5].

Absorption, Distribution and Excretion
Approximately 28% of the oral dose is absorbed; however, due to a significant first-pass effect, only 6% of the oral dose enters the systemic circulation unchanged. Bromocriptine and its metabolites appear in the blood within 10 minutes after oral administration and reach peak plasma concentrations within 1–1.5 hours. Serum prolactin levels may decrease within 2 hours after oral administration, reaching their maximum effect after 8 hours. In patients with acromegaly, a single oral dose of 2.5 mg results in a decrease in growth hormone concentrations within 1–2 hours, with the decreased concentration lasting at least 4–5 hours. The parent drug and its metabolites are almost entirely excreted by the liver, with only 6% excreted by the kidneys. Metabolism/Metabolites Completely metabolized in the liver, primarily through amide bond hydrolysis to produce lysergic acid and peptide fragments, both of which are inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and is primarily excreted in feces via bile secretion.
The known human metabolites of bromocriptine include 5-bromo-N-[2,10-dihydroxy-7-(2-methylpropyl)-5,8-dioxo-4-propyl-2-yl-3-oxa-6,9-diazatricyclo[7.3.0.02,6]dodecano-4-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolano[4,3-fg]quinoline-9-carboxamide and 5-bromo-N-[2,11-dihydroxy-7-(2-methylpropyl)-5,8-dioxo-4-propyl-2-yl-3-oxa-6,9-diazatricyclo[7.3.0.02,6]dodecano-4-yl]-7-methyl-6,6a,8,9-tetrahydro-4H-indolano[4,3-fg]quinoline-9-carboxamide. Bromocriptine is completely metabolized in the liver, primarily through amide bond hydrolysis to produce lysergic acid and peptide fragments, both of which are inactive and non-toxic. Bromocriptine is metabolized by cytochrome P450 3A4 and excreted mainly through bile in feces. Excretion pathway: The original drug and its metabolites are almost entirely excreted by the liver, with only 6% excreted by the kidneys. Half-life: 2-8 hours.

Toxicity Summary
The dopamine D2 receptor is a 7-transmembrane G protein-coupled receptor associated with Gi proteins. In lactating cells, activation of the dopamine D2 receptor leads to inhibition of adenylate cyclase, thereby reducing intracellular cAMP concentration and blocking the release of IP3-dependent Ca2+ from intracellular stores. The reduction in intracellular calcium levels may also be achieved through inhibition of calcium influx into voltage-gated calcium channels rather than inhibition of adenylate cyclase. Furthermore, receptor activation blocks phosphorylation of p42/p44 MAPK and reduces phosphorylation of MAPK/ERK kinases. MAPK inhibition appears to be mediated by c-Raf and β-Raf-dependent MAPK/ERK kinase inhibition. Dopamine-stimulated pituitary release of growth hormone is mediated by reduced intracellular calcium ion influx through voltage-gated calcium channels, rather than by inhibition of adenylate cyclase. Stimulation of dopamine D2 receptors in the substantia nigra-striatal pathway can improve muscle coordination in patients with movement disorders. Ergoline alkaloids have been shown to have significant affinity for serotonin receptors 5-HT1 and 5-HT2, dopamine D1 and D2, and α-adrenergic receptors. This can lead to a variety of effects, including vasoconstriction, seizures, and hallucinations. Bromocriptine exerts its effects by directly stimulating dopamine receptors in the striatum. (A2914, A2915, A2916, A2941)

[1]. Gardner B, et al. Agonist action at D2(long) dopamine receptors: ligand binding and functional assays. Br J Pharmacol. 1998 Jul;124(5):978-84.
[2]. Renodon A, et al. Bromocriptine is a strong inhibitor of brain nitric oxide synthase: possible consequences for the origin of its therapeutic effects.FEBS Lett. 1997 Apr 7;406(1-2):33-6.
[3]. Wynalda MA, et al. Assessment of potential interactions between dopamine receptor agonists and various human cytochrome P450 enzymes using a simple in vitro inhibition screen. Drug Metab Dispos. 1997 Oct;25(10):1211-4.
[4]. Rana DG, et al. Dopamine mediated antidepressant effect of Mucuna pruriens seeds in various experimental models of depression. Ayu. 2014 Jan;35(1):90-7.
[5]. Dieb W, et al. Nigrostriatal dopaminergic depletion increases static orofacial allodynia. J Headache Pain. 2016;17:11

Pharmacodynamics
Bromocriptine stimulates central dopaminergic receptors, thereby producing a variety of pharmacological effects. Currently, five dopamine receptors from two dopaminergic subfamilies have been identified. The dopamine D1 receptor subfamily includes D1 and D5 subreceptors, which are associated with motor disorders. The dopamine D2 receptor subfamily includes D2, D3, and D4 subreceptors, which are associated with the improvement of motor disorder symptoms. Therefore, specific agonist activity of D2 subfamily receptors (mainly D2 and D3 receptor subtypes) is a major target for dopaminergic anti-Parkinson's disease drugs. It is believed that postsynaptic D2 receptor activation is the main reason for the anti-Parkinson's disease effect of dopamine agonists, while presynaptic D2 receptor activation has a neuroprotective effect. This semi-synthetic ergot derivative exhibits potent agonist activity against dopamine D2 receptors. It also exhibits agonist activity against serotonin (5-HT)1D, dopamine D3, 5-HT1A, 5-HT2A, 5-HT1B, and 5-HT2C receptors (in descending order of binding affinity), antagonist activity against α2A-adrenergic receptors, α2C, α2B, and dopamine D1 receptors, partial agonist activity against 5-HT2B receptors, and inactivation of dopamine D4 and 5-HT7 receptors. Parkinson's disease is caused by the loss of approximately 80% dopaminergic activity in the substantia nigra-striatal pathway of the brain. Because the striatum is involved in regulating and coordinating the intensity of muscle activity (e.g., movement, balance, walking), loss of its activity can lead to dystonia (acute muscle contractions), Parkinson's syndrome (including symptoms such as bradykinesia, tremor, rigidity, and apathy), akathisia (restlessness), tardive dyskinesia (involuntary muscle movements usually associated with prolonged loss of dopaminergic activity), and neuroleptic malignancy, the latter occurring when dopamine is completely blocked in the substantia nigra-striatal pathway. Excessive dopaminergic activity in the mesolimbic pathway can lead to hallucinations and delusions; these side effects of dopamine agonists are common in patients with schizophrenia due to overactivity in this area of their brains. The hallucinogenic side effects of dopamine agonists may also be related to 5-HT2A receptor agonism. The tuberous-infundibular pathway originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits the secretion of prolactin from the anterior pituitary lactocytes. Increased dopaminergic activity in the tuberous infundibulum pathway can inhibit prolactin secretion; therefore, bromocriptine is an effective drug for treating diseases related to excessive prolactin secretion. Pulmonary fibrosis may be related to the agonistic effect of bromocriptine on 5-HT1B and 5-HT2B receptors.

C32H40BRN5O5

654.606

653.221

25614-03-3

Bromocriptine mesylate;22260-51-1

31101

Typically exists as solid at room temperature

1.52 g/cm3

891.3ºC at 760 mmHg

215-218

492.8ºC

4.15E-34mmHg at 25°C

1.696

3.397

3

6

5

43

1230

6

CC(C[C@H]1C(N2CCC[C@H]2[C@@]3(O)N1C([C@](NC([C@@H]4C=C5C6=C7C(C[C@H]5N(C4)C)=C(NC7=CC=C6)Br)=O)(O3)C(C)C)=O)=O)C

OZVBMTJYIDMWIL-AYFBDAFISA-N

InChI=1S/C32H40BrN5O5/c1-16(2)12-24-29(40)37-11-7-10-25(37)32(42)38(24)30(41)31(43-32,17(3)4)35-28(39)18-13-20-19-8-6-9-22-26(19)21(27(33)34-22)14-23(20)36(5)15-18/h6,8-9,13,16-18,23-25,34,42H,7,10-12,14-15H2,1-5H3,(H,35,39)/t18-,23-,24+,25+,31-,32+/m1/s1

Ergotaman-3',6',18-trione, 2-bromo-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-, (5'alpha)-

CB154 CB 154 Bromocriptine CB-154

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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