**Background**
The modulation of G protein-coupled receptors (GPCRs) is a fundamental strategy in treating a wide array of physiological disorders. Among these, the H1 histamine receptor and muscarinic acetylcholine receptors (mAChRs) play critical roles in regulating allergic responses, nausea, and central nervous system arousal. Furthermore, serotonin receptors, specifically the 5-HT2A and 5-HT2C subtypes, are essential targets for understanding hallucinogenic effects and mood regulation. Beyond its classical pharmacological applications, recent research has highlighted the potential of certain phenothiazine derivatives to influence adipogenesis and ectopic fat formation, opening new avenues for metabolic research. In this context, we will introduce a versatile phenothiazine derivative – Promethazine.
**Definition**
Promethazine is an orally active phenothiazine derivative that acts as a potent H1 receptor antagonist and mAChR antagonist, while also exhibiting affinity for 5-HT2A and 5-HT2C receptors.
**In Vitro and In Vivo Studies**
According to the Promethazine description, this compound possesses a variety of antihistaminic, sedative, antiemetic, and anticholinergic properties. Promethazine in vitro studies have demonstrated its impact on metabolic processes; specifically, concentrations of 1.25-10 μM over 3 days inhibit adipocyte formation in a dose-dependent manner. Furthermore, treatment with 10 μM for 0-12 days decreases the expression of peroxisome proliferator activated receptor γ (PPARG) and reduces the phosphorylation level of CREB in PDGFRα+ cells. Regarding cellular toxicity, Promethazine biological activity in L929 lung fibroblast cells shows cytotoxic effects at concentrations exceeding 100 μM within 1-24 hours. Additionally, in SARS-CoV-2 infected Vero E6 cells, Promethazine exhibits IC50 values of 9.21 μM (at MOI 0.004) and 10.44 μM (at MOI 0.01), with CC50 values > 42.59 μM.
Promethazine In Vivo research has further explored its therapeutic potential. In a mouse achilles tendon rupture model, administration of 0.05-0.1 mg/mL via oral gavage for 4 weeks showed an inhibitory effect on the formation of ectopic fat cells in skeletal muscle. In other studies, doses of 2.4-9.6 mg/kg (p.o.) in adult castrate male rats were found to have no effect on the development of femoral osteoporosis, although they retarded normal femoral expansion. In conclusion, Promethazine is a multi-target antagonist with significant applications in antihistamine, antiemetic, and metabolic research.
Keywords
Promethazine, 58-33-3, Histamine Receptor, mAChR, Adrenergic Receptor, Muscarinic acetylcholine receptor, Beta Receptor, antihistaminic (H1), sedative, antiemetic, anticholinergic, antimotion sickness, H1 receptor antagonist, Inhibitor, inhibitor
References
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[2] Kasai T, et al. Promethazine Hydrochloride Inhibits Ectopic Fat Cell Formation in Skeletal Muscle. Am J Pathol. 2017 Dec;187(12):2627-2634.
[3] McDonough JA, et al. Microcapsule-gel formulation of promethazine HCl for controlled nasal delivery: a motion sickness medication. J Microencapsul. 2007 Mar;24(2):109-16.
[4] Wink CS, et al. Effects of promethazine HCl on osteoporotic femora of adult castrated male rats. Acta Anat (Basel).