ABSTRACT
BackgroundClinical ophthalmological guidelines encourage the assessment of potential benefits and harms when deciding whether to perform elective ophthalmology procedures during the COVID-19 pandemic, in order to minimize the risk of disease transmission. MethodWe performed probability calculations to estimate COVID-19 infection status and likelihood of disease transmission among neovascular age-related macular degeneration patients and health care workers during anti-VEGF procedures, at various community prevalence levels of COVID-19. We then applied the expected burden of COVID-19 illness and death expressed through health-adjusted life-years (HALYs) lost. We compared these results to the expected disease burden of severe visual impairment if sight protecting anti-VEGF injections were not performed. ResultsOur calculations suggest a wide range of contexts where the benefits of treatment to prevent progression to severe visual impairment or blindness are greater than the expected harms to the patient and immediate health care team due to COVID-19. For example, with appropriate protective equipment the benefits of treatment outweigh harms when the chance of progression to severe visual impairment is >0.044% for all scenarios where COVID-19 prevalence was one per thousand, even when the attack rate in the clinical setting is very high (5-43%). ConclusionUnless COVID-19 prevalence is very high, the reduced disease burden from avoiding visual impairment outweighs the expected HALYs lost from COVID-19 transmission. This finding is driven by the fact that HALYs lost when someone suffers severe visual impairment for 5 years are equivalent to nearly 400 moderate cases of infectious disease lasting 2 weeks each.
ABSTRACT
As part of our ongoing efforts to identify novel ligands for the metabotropic glutamate 2 and 3 (mGlu2/3) receptors, we have incorporated substitution at the C3 and C4 positions of the (1S,2R,5R,6R)-2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid scaffold to generate mGlu2/3 antagonists. Exploration of this structure-activity relationship (SAR) led to the identification of (1S,2R,3S,4S,5R,6R)-2-amino-3-[(3,4-difluorophenyl)sulfanylmethyl]-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid hydrochloride (LY3020371·HCl, 19f), a potent, selective, and maximally efficacious mGlu2/3 antagonist. Further characterization of compound 19f binding to the human metabotropic 2 glutamate (hmGlu2) site was established by cocrystallization of this molecule with the amino terminal domain (ATD) of the hmGlu2 receptor protein. The resulting cocrystal structure revealed the specific ligand-protein interactions, which likely explain the high affinity of 19f for this site and support its functional mGlu2 antagonist pharmacology. Further characterization of 19f in vivo demonstrated an antidepressant-like signature in the mouse forced-swim test (mFST) assay when brain levels of this compound exceeded the cellular mGlu2 IC50 value.
Subject(s)
Antidepressive Agents/pharmacology , Behavior, Animal/drug effects , Drug Discovery , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Antidepressive Agents/chemical synthesis , Antidepressive Agents/chemistry , Brain/drug effects , Cyclohexanes/chemical synthesis , Cyclohexanes/chemistry , Cyclohexanes/pharmacology , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Inbred Strains , Models, Molecular , Molecular Structure , Motor Activity/drug effects , Receptors, Metabotropic Glutamate/chemistry , Receptors, Metabotropic Glutamate/isolation & purification , Structure-Activity Relationship , SwimmingABSTRACT
Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo[3.1.0]hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
Subject(s)
Antidepressive Agents/chemistry , Antidepressive Agents/pharmacology , Depressive Disorder, Major/drug therapy , Glutamic Acid/analogs & derivatives , Glutamic Acid/pharmacology , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Animals , Antidepressive Agents/pharmacokinetics , Bridged Bicyclo Compounds/chemistry , Bridged Bicyclo Compounds/pharmacokinetics , Bridged Bicyclo Compounds/pharmacology , Cell Line , Depressive Disorder, Major/metabolism , Dogs , Glutamic Acid/pharmacokinetics , Haplorhini , Hexanes/chemistry , Hexanes/pharmacokinetics , Hexanes/pharmacology , Humans , Madin Darby Canine Kidney Cells , Mice , Rats , Receptors, Metabotropic Glutamate/metabolismABSTRACT
A structurally unique and new class of opioid receptor antagonists (OpRAs) that bear no structural resemblance with morphine or endogenous opioid peptides has been discovered. A series of carboxamido-biaryl ethers were identified as potent receptor antagonists against mu, kappa and delta opioid receptors. The structure-activity relationship indicated para-substituted aryloxyaryl primary carboxamide bearing an amine tether on the distal phenyl ring was optimal for potent in vitro functional antagonism against three opioid receptor subtypes.
