{'fraction_non_alphanumeric': 0.05413584398117014, 'fraction_numerical': 0.03026227303295225, 'mean_word_length': 5.384120171673819, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 5, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Serotonin-2 receptor agonists as novel ocular hypotensive agents and their cellular and molecular mechanisms of action.

The eye is innervated by numerous serotonergic nerves and serotonin (5-hydroxytryptamine; 5HT) is present in the aqueous humor of animal and human eyes. In an effort to delineate the role of the serotonergic system in modulating intraocular pressure (IOP) within the anterior segment of the eye, extensive topical ocular dosing studies were conducted with a variety of 5HT ligands and in various animal species. Even though certain 5HT(1A) agonists decreased IOP in rabbits, these compounds failed to affect IOP in normotensive or ocular hypertensive monkey eyes. In contrast, while 5HT(2) agonists induced significant IOP reductions in normotensive rat eyes and in eyes of ocular hypertensive Cynomolgus monkeys, these agents were inactive in ocular normotensive cats and rabbits. Additional studies indicated a strong involvement of 5HT(2A) receptors in mediating IOP-lowering in conscious ocular hypertensive Cynomolgus monkeys. As a result of further structure-activity investigations, AL-34662, a selective 5HT(2) agonist (relative to other 5HT receptor types and sub-types) with high affinity, potency and efficacy at 5HT(2A), 5HT(2B) and 5HT(2C) receptors was discovered that efficaciously lowered IOP in the monkey model of ocular hypertension (33 +/- 3 % reduction out to 6 hrs post with a 300 microg topical ocular dose). Due to unavailability of monkey ocular cells, extensive in vitro studies were conducted using relevant human ocular cells in order to correlate with and support the in vivo observations in the monkeys. RT-PCR and in situ hybridization studies revealed the presence of mRNAs for 5HT(2A-C) receptor subtypes in human ocular tissues involved in IOP modulation. The relative distribution and density of these mRNAs were as follows: ciliary body (CB) (5HT(2A) > 5HT(2B) > 5HT(2C)), ciliary epithelium (CE) (5HT(2A) > 5HT(2B) = 5HT(2C)) and trabecular meshwork (TM) (5HT(2A)= 5HT(2B) >> 5HT(2C)). Furthermore, quantitative autoradiography revealed a relatively high specific binding of [(3)H]-5HT and [(3)H]-ketanserin to 5HT(2) receptors in human CE and longitudinal ciliary muscle (CM). Second messenger studies revealed the presence of phospholipase C-coupled 5HT(2A) receptors in h-CM and h-TM cells where they stimulated phosphoinositide (PI) hydrolysis and mobilized intracellular Ca(2+) when challenged with a variety of 5HT(2A-C) receptor agonists (e.g. alpha-methyl-5HT, (R)-DOI, alpha-methyl-5HT, BW-723C86, MK-212, mCPP, cabergoline, AL-34662). These functional responses were blocked by selective 5HT(2) receptor antagonists with the 5HT(2A) antagonist, M-100970, exhibiting the highest potency. Thus, functional 5HT(2A) receptors are present in human ocular cells involved in IOP reduction and this correlates with the ability of 5HT(2A) agonists to lower IOP in Cynomolgus monkeys, a surrogate for human subjects.