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 |