piperidines and Glaucoma

Acetylcholinesterase (AChE) inhibitors are an important class of medicinal agents useful for the treatment of Alzheimer s disease, glaucoma, myasthenia gravis and for the recovery of neuromuscular block in surgery. To rationalize the structural requirements of AChE inhibitors we attempt to derive a coherent AChE-inhibitor recognition pattern based on literature data of molecular modelling and quantitative structure-activity relationship (QSAR) analyses. These data are summarised from nearly all therapeutically important chemical classes of reversible AChE inhibitors, e.g., derivatives of physostigmine, tacrine, donepezil and huperzine A. Interactions observed from X-ray crystallography between these inhibitors and AChE have also been incorporated and compared with modelling and QSAR results. It is concluded that hydrophobicity and the presence of an ionizable nitrogen are the pre-requisites for the inhibitors to interact with AChE. However the mode of interaction i.e., the 3-dimensional (3D) positioning of the inhibitor in the active site of the enzyme varies among different chemical classes. It is also recognised that water molecules play crucial roles in defining these different 3D positioning. The information on AChE-inhibitor interactions provided should be useful for future discovery of new chemical classes of AChE inhibitors, especially from De Novo design and hybrid construction.

Topics: Alkaloids; Alzheimer Disease; Cholinesterase Inhibitors; Crystallography, X-Ray; Donepezil; Drug Design; Glaucoma; Humans; Indans; Models, Molecular; Myasthenia Gravis; Neostigmine; Physostigmine; Piperidines; Sesquiterpenes; Structure-Activity Relationship; Surface Properties; Tacrine

Topics: Amitriptyline; Analgesics; Antidepressive Agents; Chlorpromazine; Diazepam; Diphenhydramine; Eye Diseases; Glaucoma; Histamine H1 Antagonists; Humans; Imipramine; Intraocular Pressure; Lithium; Mental Disorders; Mephenesin; Meprobamate; Piperidines; Psychotropic Drugs; Secologanin Tryptamine Alkaloids; Tranquilizing Agents; Trihexyphenidyl

Optic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Glaucoma; Mitochondria; Neuroprotective Agents; Piperidines; Rats; Reactive Oxygen Species; Receptors, sigma; Retinal Ganglion Cells; Sigma-1 Receptor

Monoacylglycerol lipase (MGL) inhibition provides a potential treatment approach to glaucoma through the regulation of ocular 2-arachidonoylglycerol (2-AG) levels and the activation of CB1 receptors. Herein, we report the discovery of new series of carbamates as highly potent and selective MGL inhibitors. The new inhibitors showed potent nanomolar inhibitory activity against recombinant human and purified rat MGL, were selective (>1000-fold) against serine hydrolases FAAH and ABHD6 and lacked any affinity for the cannabinoid receptors CB1 and CB2. Protein-based

Topics: Animals; Carbamates; Catalytic Domain; Enzyme Inhibitors; Glaucoma; Humans; Male; Mice, Inbred C57BL; Microsomes, Liver; Molecular Docking Simulation; Molecular Structure; Monoacylglycerol Lipases; Piperazines; Piperidines; Rats; Structure-Activity Relationship

The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate.. Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354.. sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost)-induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted.. MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies.

Topics: Administration, Ophthalmic; Animals; Antihypertensive Agents; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Activators; Glaucoma; Humans; Immunohistochemistry; Intraocular Pressure; Macaca fascicularis; Ocular Hypotension; Ophthalmic Solutions; Piperidines; Pyrazoles; Pyridines; Rabbits; Soluble Guanylyl Cyclase; Trabecular Meshwork

It was previously shown that EphB/ephrinB reverse signaling in retinal ganglion cells (RGCs) is activated and involved in RGC apoptosis in a rat chronic ocular hypertension (COH) model. In the present work, we first show that ephrinB/EphB forward signaling was activated in COH retinas, and RGC apoptosis in COH retinas was reduced by PP2, an inhibitor of ephrinB/EphB forward signaling. We further demonstrate that treatment of cultured Müller cells with ephrinB1-Fc, an EphB1 activator, or intravitreal injection of ephrinB1-Fc in normal rats induced an increase in phosphorylated EphB levels in these cells, indicating the activation of ephrinB/EphB forward signaling, similar to those in COH retinas. The ephrinB1-Fc treatment did not induce Müller cell gliosis, as evidenced by unchanged GFAP expression, but significantly up-regulated mRNA and protein levels of tumor necrosis factor-α (TNF-α) in Müller cells, thereby promoting RGC apoptosis. Production of TNF-α induced by the activation of ephrinB/EphB forward signaling was mediated by the NR2B subunit of NMDA receptors, which was followed by a distinct PI3K/Akt/NF-κB signaling pathway, as pharmacological interference of each step of this pathway caused a reduction of TNF-α production, thus attenuating RGC apoptosis. Functional analysis of forward and reverse signaling in such a unique system, in which ephrin and Eph exist respectively in a glial element and a neuronal element, is of theoretical importance. Moreover, our results also raise a possibility that suppression of ephrinB/EphB forward signaling may be a new strategy for ameliorating RGC apoptosis in glaucoma.

Topics: Animals; Animals, Newborn; Antioxidants; Apoptosis; Cells, Cultured; Chromones; Disease Models, Animal; Ephrin-B1; Excitatory Amino Acid Agents; Glaucoma; Glial Fibrillary Acidic Protein; Intercellular Signaling Peptides and Proteins; Male; Morpholines; Phenols; Piperidines; Proline; Pyrimidines; Rats; Rats, Sprague-Dawley; Receptors, Eph Family; Receptors, N-Methyl-D-Aspartate; Retinal Ganglion Cells; Signal Transduction; Thiocarbamates; Tumor Necrosis Factor-alpha

A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide.

Topics: Animals; Antihypertensive Agents; Carbon Disulfide; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Disease Models, Animal; Glaucoma; Humans; Intraocular Pressure; Male; Molecular Docking Simulation; Morpholines; Piperazines; Piperidines; Quinuclidines; Rabbits; Structure-Activity Relationship; Substrate Specificity; Sulfonamides; Thiocarbamates; Thiophenes

Topics: Anesthesia, General; Anesthetics, Intravenous; Elective Surgical Procedures; Female; Glaucoma; Humans; Middle Aged; Piperidines; Propofol; Remifentanil; Trismus

Topics: Airway Obstruction; Anesthetics, Inhalation; Anesthetics, Intravenous; Failure to Thrive; Fiber Optic Technology; Glaucoma; Humans; Infant; Intellectual Disability; Intubation, Intratracheal; Laryngeal Masks; Male; Maxillofacial Abnormalities; Methyl Ethers; Monitoring, Physiologic; Piperidines; Rare Diseases; Remifentanil; Sevoflurane; Syndrome

To assess the neuroprotective effects of different glutamate modulation strategies, with a nonselective (MK801) and a selective (ifenprodil) NMDA receptor antagonist and a metabotropic glutamate receptor agonist (mGluR Group II, LY354740), in glaucoma-related in vivo rat models of retinal ganglion cell (RGC) apoptosis.. RGC apoptosis was induced in Dark Agouti (DA) rats by staurosporine (SSP) treatment. Single agents MK801, ifenprodil, or LY354740, or MK801 and LY354740 combined, were administrated intravitreally at different doses. Eyes were imaged in vivo using a recently established technique and the results confirmed histologically. The most effective combined therapy regimen of MK801 and LY354740 was then assessed in a chronic ocular hypertension (OHT) rat model with application at 0, 1, and 2 weeks after OHT surgery and the effects assessed as described before.. All strategies of glutamate modulation reduced SSP-induced-RGC apoptosis compared with the control, in a dose-dependent manner: MK801 (R2= 0.8863), ifenprodil (R2= 0.4587), and LY354740 (R2= 0.9094), with EC50s of 0.074, 0.0138, and 19 nanomoles, respectively. The most effective combination dose of MK801 and LY354740 was 0.06 and 20 nanomoles (P < 0.05), respectively, and the optimal timing of the therapy was 0 weeks after OHT surgery (P < 0.05).. This novel SSP model was validated as a useful tool for screening neuroprotective strategies in vivo. Group II mGluR modulation may be a useful treatment for RGC death. Combination therapy optimized to limit neurotoxic effects of MK801 may be an effective neuroprotective approach in retinal degenerative disease. Furthermore, treatments that minimize secondary RGC degeneration may be most useful in glaucoma.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glaucoma; Glutamic Acid; Intraocular Pressure; Male; Neuroprotective Agents; Ocular Hypertension; Piperidines; Rats; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Retinal Ganglion Cells; Staurosporine

A pilot study of the possible anticholinergic side effects of femoxetine comprised eight depressive patients (age 42-65), followed up for a month, and five healthy volunteers (age 26-39), who received medication for a week. As judged primarily from ophthalmic parameters (accomodation, lacrimation, pupil size, intraocular pressure, exe motility, visual acuity and visual fields, slit lamp examination and ophthalmoscopy), there was no indication of anticholinergic side effects of the drug. According to Schirmer-1-test (tear wetting), the rather dry eyes of depressive patients even improved somewhat during medication.

Topics: Adult; Aged; Antidepressive Agents; Eye Diseases; Female; Glaucoma; Humans; Male; Middle Aged; Piperidines; Tears; Vision Disorders; Xerophthalmia

Topics: Anesthesia, Local; Anesthetics, Local; Anilides; Cataract Extraction; Glaucoma; Humans; Ophthalmologic Surgical Procedures; Piperidines; Xylenes

Topics: Benzilates; Female; Glaucoma; Humans; Male; Muscles; Piperidines; Prostatic Hyperplasia; Urinary Bladder Diseases

Topics: Adult; Analgesics; Chlorpromazine; Diphenhydramine; Glaucoma; Humans; Injections, Intramuscular; Male; Piperidines

Topics: Alkaloids; Azepines; Glaucoma; Heterocyclic Compounds, Bridged-Ring; Humans; Lactones; Myasthenia Gravis; Ophthalmology; Optic Atrophy; Piperidines; Retina; Vision Tests; Visual Fields

Topics: Anesthesia; Anesthesia, General; Anesthetics; Animals; Cercopithecus; Chlorocebus aethiops; Glaucoma; Haplorhini; Lidocaine; Manometry; Ophthalmoscopy; Pentobarbital; Phencyclidine; Piperidines; Research; Tonometry, Ocular