Cabergoline: An Efficacious Multivalent Ocular Hypotensive Agent

Abstract

Purpose:: To determine the in vitro and in vivo ocular and non-ocular pharmacological properties of cabergoline.

Methods:: 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.

Results:: Cabergoline bound to native and /or human cloned serotonin-2A/B/C (5HT_2A/B/C), 5HT_1A, 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, 5HT_1A (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 5HT_2A (EC₅₀ = 63 nM), 5HT_2B (EC₅₀ = 1 µM) and 5HT_2C (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.

Conclusions:: Cabergoline exhibited a variety of pharmacological activities in cultured cells and in radioligand binding assays. Its most prominent agonist activity involved activation of 5HT₂, 5HT_1A and DA-2/3 receptors, while it behaved as an antagonist at the 5HT₇ and α2-adrenoceptors. Since 5HT_1A 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.

Keywords: receptors: pharmacology/physiology • outflow: ciliary muscle • intraocular pressure