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. 2021 Sep 17;12:729249. doi: 10.3389/fphar.2021.729249

TABLE 2.

Some examples of recently discovered IOP-lowering agents and their potential mechanisms of actions in various animal models of OHT.

Compound classes Investigative agent Reported or potential mechanism(s) of action (MOA)
Conventional Outflow (via TM pathway) Promotors
 Inhibitors of chloride transport Ticrynafen; Ethacrynic acid; Indacrinone Inhibition of Na+-K+-Cl--transporter activity in the TM changes cell shape and volume and thus AQH efflux is increased
 Kinase inhibitors Chelerythrine; Staurosporin; LIM-K inhibitors (e.g., LX7101); Myosin-II ATPase inhibitor: Blebbistatin. Src kinase inhibitor Modification of actomyosin contractility that leads to changes in actin cytoskeleton of TM and this leads to AQH efflux; direct relaxation of the TM may also be involved
 Rho Kinase Inhibitors Fasudil; Y-27632; AMA0076; ITRI-E-212 Modification of actomyosin contractility that leads to changes in actin cytoskeleton of TM and this leads to AQH efflux; direct relaxation of the TM may also be involved
 Marine macrolids Latrunculins A and B; Bumetanide; Swinholide Promote sequestration of actin monomers and dimers in TM; cause cell TM shape change and thus AH efflux
 Guanylate cyclase activators Natriuretic peptides and constrained cyclic peptides: ANP; CNP; TAK-639 Type-A and type-B receptor activation leads to cGMP production, TM relaxation and AQH efflux via TM.
 NO Donors Sodium nitroprusside; Hydralazine; 3-morpholinosyndnonimine; (S)-nitrosoacetylpenicillamine; NCX-125 NO activates intracellular soluble guanylate cyclase to increase cGMP production, TM relaxation and AQH efflux via TM.
 Soluble guanylate cyclase activators IWP-953; MGV354 These compounds directly activate intracellular soluble guanylate cyclase to increase cGMP production, TM relaxation and AQH efflux via TM.
 κ-opioid receptor agonists Bremazocine; Dynorphin Release natriuretic peptides and thus raise cGMP in TM leading to its relaxation and thus AQH efflux
 Cannabinoid receptor agonists WIN55212-2; CP55940; SR141716A Receptor stimulation opens BKC-channels and relaxes TM which then causes AQH efflux via TM and SC
 Serotonin-2 receptor antagonists BVT-28949; Ketanserin and its analogs Unknown and unverifiable mechanism(s) of action (may block beta-adrenergic receptors indirectly?)
 Releasers of MMP & AP-1 t-butylhydroquinone (t-BHQ); β-naphthoflavone Local production of MMPs; ECM degradation; stimulation of AQH efflux via TM/SC
 Autotaxin/Lysophosphatidic acid inhibitors Aiprenon Promotion of AQH egress from TM/SC pathway
Uveoslceral Outflow promotors (via CM bundles and sclera)
 EP2- and EP4- PG-receptor agonists AL-6598; Butaprost; ONO-AE1-259–01; PF-04217329; PF-04475270 Receptor activation increases cAMP that relaxes CM & TM; EP2 agonists also cause release of MMPs that breakdown ECM (“clog”) around CM bundles and within sclera thus causing UVS outflow of AQH
 Serotonin-2 (5HT-2) receptor agonists (R)-DOI; α-methyl-5HT; AL-34662 Contraction/relaxation of CM and TM by activation of 5HT2 receptors. May also release MMPs and/or PGs or other local mediators that promote CM remodeling and thus promote UVS outflow
 Bradykinin B2-receptor agonists Bradykinin; FR-190997; BKA278 B2-receptor activation causes PI hydrolysis production of IPs and DAG; cause PG release and release of MMPs that digest ECM and this promote UVS outflow in cynomolgus monkey; conventional outflow also stimulated in isolated bovine/porcine anterior eye segments [177,178]
 Dual pharmacophore PGs FP/EP3 receptor agonist (ONO-954) Promote UVSC outflow
Inflow inhibitors (reduce AQH production)
 Chloride channels inhibitors 5-nitro-2-(3-phenylpropylamino)-benzoate (NPPB) Ion flux of CP NPE cells causes reduction of AQH formation
 Na+-K+-ATPase inhibitors Ouabain; Digoxin analogs Ciliary process Na+-K+-ATPase inhibited leading to inhibition of AQH production
 Dopamine receptor agonists PD128907; CHF1035; CHF1024; SDZ GLC-756; (S)-(-)-3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) Inhibit release of NE & prevent AQH production; may also release natriuretic peptides
 Na+-K+-ATPase inhibitors Ouabain; Digoxin analogs Ciliary process Na+-K+-ATPase inhibited leading to inhibition of AQH production
 Aquaporin Inhibitors Various aromatic sulfonamides and dihydrobenzofurans Inhibit release of NE & prevent AQH production
Other IOP-lowering agents
 Mas receptor stimulator DIZE via ACE-2 activation Prevent ECM (including TGFβ) accumulation (outflow stimulation ?)
 Angiotensin-II receptor antagonists CS-088 Various mechanisms of action; not robust IOP-lowering
 Ca2+-channel inhibitors Lomerazine; Nivaldipine; nifedipine; Nimodipine; Verapamil; Brovincamine; Iganidipine Enhance retinal blood flow; some may lower IOP; work well in normal tension glaucoma patients
 Alpha-adrenergic receptor antagonists Oxymetazoline; 5-methylurapidil; Ketanserin Work mostly via outflow mechanism but this needs to be defined
 ATP-sensitive K+-channel activators Cromakalim; Levocromakalim; CKPL1 Purported MOA involving episcleral veinous pressure modulation