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N. A. Sharif, C. R. Kelly, P. Katoli, G. W. Williams, C. Drace, J. Y. Crider, M. A. McLaughlin; Cabergoline: An Efficacious Multivalent Ocular Hypotensive Agent. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4897.
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© ARVO (1962-2015); The Authors (2016-present)
To determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline.
Previously published in vitro and in vivo assays and models were utilized to profile the receptor binding and functional activities of cabergoline and other key reference compounds.
Cabergoline bound to native and /or human cloned serotonin-2A/B/C (5HT2A/B/C), 5HT1A, 5HT7, α2b, dopamine-2 / 3 (DA-2/3) receptor subtypes with nanomolar affinity (IC50s = 0.5 - 17 nM). Cabergoline was an agonist at the 5HT2, 5HT1A (EC50 = 140 nM) and DA-2/3 receptors but an antagonist at the 5HT7 and α2 receptors. In primary human ciliary muscle (h-CM) and trabecular meshwork (h-TM) cells, cabergoline stimulated phosphoinositide turnover (EC50 = 19 ± 7 nM in TM; 76 nM in h-CM) and intracellular Ca2+ ([Ca2+]i) mobilization (EC50 = 972 ± 50 nM in h-TM). It also stimulated [Ca2+]i mobilization via human cloned 5HT2A (EC50 = 63 nM), 5HT2B (EC50 = 1 µM) and 5HT2C (EC50 = 570 nM) receptors. In some experiments, cabergoline stimulated cAMP production in h-CM cells when co-incubated with forskolin (EC50 = 30-100 nM). While topical ocularly administered cabergoline failed to modulate intraocular pressure (IOP) in Dutch-Belt rabbits even at 500 µg, it was an efficacious IOP-lowering agent in the ocular hypertensive cynomolgus monkeys (peak reduction of 30.6 ± 3.6% with 50 µg 3 hrs post-dose; 30.4 ± 4.5% with 500 µg 7 hr post-dose). Cabergoline caused minimal ocular irritation.
Cabergoline exhibited a variety of pharmacological activities in cultured cells and in radioligand binding assays. Its most prominent agonist activity involved activation of 5HT2, 5HT1A and DA-2/3 receptors, while it behaved as an antagonist at the 5HT7 and α2-adrenoceptors. Since 5HT1A agonists, and 5HT7 and α2 antagonists are not known to exhibit ocular hypotensive activities in the conscious ocular hypertensive monkeys, the 5HT2 and dopaminergic agonist activities of cabergoline probably mediated the IOP reduction observed with this compound in this species. These data suggest that cabergoline produces its efficacious IOP-lowering activity by multiple mechanisms involving [Ca2+]i mobilization and by elevating levels of cAMP in the target cells and tissues via its activation of 5HT2 and DA-2/3 receptors.
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