What is Metergoline?

Metergoline is a semisynthetic ergot alkaloid. Ergot alkaloids are natural products derived from fungi that act as ligands for serotonin and dopamine receptors, possessing a diverse range of pharmacological properties and clinical applications. Clinically, Metergoline—marketed under the brand name Liserdol—has been used to treat hyperprolactinemia. Furthermore, it has been employed to alleviate symptoms in patients with premenstrual dysphoric disorder (PMDD) and has also demonstrated utility as an antifungal and antimalarial agent [1-3].

Pharmacological Actions

(1) Antagonist Activity

Research indicates that Metergoline is a selective serotonin (5-HT) antagonist, capable of effectively blocking most 5-HT receptor subtypes at relatively low doses. It exhibits the highest affinity for 5-HT2A and 5-HT2C receptors. At low doses, it does not affect noradrenergic, cholinergic, GABAergic, or dopaminergic neurotransmitter systems and has been shown to be relatively well-tolerated [2].

(2) Antimicrobial Activity

In a recent phenotypic high-throughput screen, Metergoline was identified as an inhibitor of Salmonella Typhimurium (S. Tm), a Gram-negative intracellular pathogen. Studies have shown that while Metergoline lacks in vitro activity against S. Tm in nutrient-rich MHB medium, it effectively inhibits the growth of S. Tm within macrophages and prolongs the survival of mice during systemic S. Tm infection. Its mechanism of action likely involves Metergoline serving as a substrate for the AcrAB–TolC efflux pump; its antimicrobial activity is dependent on conditions where the integrity of the outer membrane is compromised (such as the acidic, low-phosphate, low-magnesium environment found within macrophages). It exhibits limited activity against wild-type Escherichia coli and Acinetobacter baumannii; however, when combined with the outer membrane permeabilizer SPR741, its activity can be enhanced by more than 128-fold. Furthermore, the cinnamamide and arylacrylamide derivatives of metergoline demonstrate greater potency against Gram-positive bacteria than metergoline itself. Among these, a pyridine derivative has shown efficacy against methicillin-resistant Staphylococcus aureus (MRSA) in a mouse skin infection model [3].

References

[1] M.D., P. G. C., M.D., C. F., M.D., A. M., M.D., R. F., M.D., M. M., M.D., R. C., M.D., P. R., M.D., P. T., M.D., E. R. (1979). Metergoline Treatment of Hyperprolactinemic States*. Fertility and Sterility, 32 3, Pages 280-285. https://doi.org/10.1016/S0015-0282(16)44233-0

[2] Roca, C. A., Schmidt, P. J., Smith, M. J., Danaceau, M. A., Murphy, D. L., Rubinow, D. R. (2002). Effects of metergoline on symptoms in women with premenstrual dysphoric disorder. American Journal of Psychiatry, 159 11, 1876–1881. https://doi.org/10.1176/appi.ajp.159.11.1876

[3] Johnson, J. W., Ellis, M. J., Piquette, Z. A., MacNair, C., Carfrae, L., Bhando, T., Ritchie, N. E., Saliba, P., Brown*, E. D., Magolan*, J. (2022). Antibacterial Activity of Metergoline Analogues: Revisiting the Ergot Alkaloid Scaffold for Antibiotic Discovery. ACS Medicinal Chemistry Letters, 13 2, 284–291. https://doi.org/10.1021/acsmedchemlett.1c00648