Vemuri VK

References (7)

Title : Endocannabinoid regulation of homeostatic feeding and stress-induced alterations in food intake in male rats - Sticht_2019_Br.J.Pharmacol_176_1524
Author(s) : Sticht MA , Lau DJ , Keenan CM , Cavin JB , Morena M , Vemuri VK , Makriyannis A , Cravatt BF , Sharkey KA , Hill MN
Ref : British Journal of Pharmacology , 176 :1524 , 2019
Abstract : BACKGROUND AND PURPOSE: Stress is known to reduce food intake. Many aspects of the stress response and feeding are regulated by the endocannabinoid system, but the roles of anandamide (AEA) and 2-arachidonoyl glycerol (2-AG) in stress-induced anorexia are unclear. EXPERIMENTAL APPROACH: Effects of acute restraint stress on endocannabinoids were investigated in male Sprague-Dawley rats. Systemic and central pharmacological inhibition of fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL) was used to assess the effects of elevated AEA and 2-AG on homeostatic feeding and on food consumption after stress. Animals were pretreated with the FAAH inhibitor, PF-04457845, or the MAGL inhibitor, MJN110, before 2 h acute restraint stress or 2 h homecage period without food. KEY RESULTS: Restraint stress decreased hypothalamic and circulating AEA, with no effect in the gastrointestinal tract, while 2-AG content in the jejunum (but not duodenum) was reduced. PF-04457845 (30 microg), given i.c.v., attenuated stress-induced anorexia via CB(1) receptors, but reduced homeostatic feeding in unstressed animals through an unknown mechanism. On the other hand, systemic administration of MJN110 (10 mg.kg(-1) ) reduced feeding, regardless of stress or feeding status and inhibited basal intestinal transit in unstressed rats. The ability of MAGL inhibition to reduce feeding in combination with stress was independent of CB(1) receptor signalling in the gut as the peripherally restricted CB(1) receptor antagonist, AM6545 did not block this effect. CONCLUSIONS AND IMPLICATIONS: Our data reveal diverse roles for 2-AG and AEA in homeostatic feeding and changes in energy intake following stress. LINKED ARTICLES: This article is part of a themed section on 8(th) European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc.
ESTHER : Sticht_2019_Br.J.Pharmacol_176_1524
PubMedSearch : Sticht_2019_Br.J.Pharmacol_176_1524
PubMedID: 30051485

Title : Medicinal chemistry of cannabinoids - Vemuri_2015_Clin.Pharmacol.Ther_97_553
Author(s) : Vemuri VK , Makriyannis A
Ref : Clinical Pharmacology & Therapeutics , 97 :553 , 2015
Abstract : The endocannabinoid system comprises the two well characterized Gi/o -protein coupled receptors (cannabinoid receptor 1 (CB1) and CB2), their endogenous lipid ligands, and the enzymes involved in their biosynthesis and biotransformation. Drug discovery efforts relating to the endocannabinoid system have been focused mainly on the two cannabinoid receptors and the two endocannabinoid deactivating enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MGL). This review provides an overview of cannabinergic agents used in drug research and those being explored clinically.
ESTHER : Vemuri_2015_Clin.Pharmacol.Ther_97_553
PubMedSearch : Vemuri_2015_Clin.Pharmacol.Ther_97_553
PubMedID: 25801236

Title : Analysis of tolerance and behavioral\/physical dependence during chronic CB1 agonist treatment: effects of CB1 agonists, antagonists, and noncannabinoid drugs - Desai_2013_J.Pharmacol.Exp.Ther_344_319
Author(s) : Desai RI , Thakur GA , Vemuri VK , Bajaj S , Makriyannis A , Bergman J
Ref : Journal of Pharmacology & Experimental Therapeutics , 344 :319 , 2013
Abstract : Behavioral studies of chronic CB(1) receptor activation may provide a pharmacological approach to understanding efficacy-related differences among CB(1) ligands as well as mechanistic commonalities between cannabinoid and noncannabinoid drugs. In the present studies, the effects of CB(1) agonists [(6aR,10aR)-3-(1-adamantyl)-6,6,9-trimethyl-6a,7,10,10a-tetrahydrobenzo[c]chromen -1-ol (AM411), 9beta-(hydroxymethyl)-3-(1-adamantyl)-hexahydrocannabinol (AM4054), R-(+)-[2,3-dihydro-5-methyl-3-[(morpholinyl)methyl]pyrrolo[1,2,3-de]-1,4-benzoxaz inyl]-(1-naphthalenyl)methanone mesylate (WIN55,212.2), Delta(9)-tetrahydrocannabinol (Delta(9)-THC), (R)-(+)-arachidonyl-1'-hydroxy-2'-propylamide (methanandamide)], CB(1) antagonists [5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazo le-3-carboxamide (SR141716A), 5-(4-alkylphenyl)-1-(2,4-dichlorophenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole- 3-carboxamide (AM4113)], and dopamine (DA)-related [methamphetamine, (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF82958), (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390), (6aR)-5,6,6a,7-tetrahydro-6-propyl-4H-dibenzo[de,g]quinoline-10,11-diol (R-(-)-NPA), haloperidol] and opioid (morphine, naltrexone) drugs on scheduled-controlled responding under a 30-response fixed ratio schedule of stimulus-shock termination in squirrel monkeys were compared before and during chronic treatment with the long-acting CB(1) agonist AM411 (1.0 mg/kg per day, i.m.). Prechronic treatment with all drugs except naltrexone (1-10 mg/kg) produced dose-related decreases in responses rates. Dose-response re-determinations during chronic treatment revealed the following: 1) >250-fold (AM411, methanandamide) and >45-fold (AM4054, WIN55,212.2, Delta(9)-THC) rightward shifts in the ED(50) values for CB(1) agonists; 2) >100-fold and >20-fold leftward shifts in the ED(50) values for SR141716A and AM4113, respectively; and 3) approximately 4.8-fold and 10-fold rightward shifts in the ED(50) values for methamphetamine and the DA D(2) agonist R-(-)-NPA, respectively. Dose-response relationships for other DA-related and opioid drugs were unchanged by chronic CB(1) agonist treatment. Differences in the magnitude of tolerance among CB(1) agonists during chronic treatment may be indicative of differences in their pharmacological efficacy, whereas the enhanced sensitivity to behaviorally disruptive effects of CB(1) antagonists may provide evidence for CB(1)-related behavioral and/or physical dependence. Finally, the development of cross-tolerance to methamphetamine and R-(-)-NPA bolsters previous evidence of interplay between CB(1) and DA D(2) signaling mechanisms.
ESTHER : Desai_2013_J.Pharmacol.Exp.Ther_344_319
PubMedSearch : Desai_2013_J.Pharmacol.Exp.Ther_344_319
PubMedID: 23197773

Title : Active-site inhibitors modulate the dynamic properties of human monoacylglycerol lipase: a hydrogen exchange mass spectrometry study - Karageorgos_2013_Biochemistry_52_5016
Author(s) : Karageorgos I , Wales TE , Janero DR , Zvonok N , Vemuri VK , Engen JR , Makriyannis A
Ref : Biochemistry , 52 :5016 , 2013
Abstract : Human monoacylglycerol lipase (hMGL) regulates endocannabinoid signaling primarily by deactivating the lipid messenger 2-arachidonoylglycerol. Agents that carbamylate hMGLs catalytic Ser(122) constitute a leading class of therapeutically promising hMGL inhibitors. We have applied peptide-level hydrogen/deuterium exchange mass spectrometry to characterize hMGL's conformational responses to two potent carbamylating inhibitors, AM6580 (irreversible) and AM6701 (slowly reversible). A dynamic, solvent-exposed lid domain is characteristic of hMGL's solution conformation. Both hMGL inhibitors restricted backbone enzyme motility in the active-site region and increased substrate binding-pocket solvent exposure. Covalent reaction of AM6580 with hMGL generates a bulkier carbamylated Ser(122) residue as compared to the more discrete Ser(122) modification by AM6701, a difference reflected in AM6580's more pronounced effect upon hMGL conformation. We demonstrate that structurally distinct carbamylating hMGL inhibitors generate particular conformational ensembles characterized by region-specific hMGL dynamics. By demonstrating the distinctive influences of two hMGL inhibitors on enzyme conformation, this study furthers our understanding at the molecular level of the dynamic features of hMGL interaction with small-molecule ligands.
ESTHER : Karageorgos_2013_Biochemistry_52_5016
PubMedSearch : Karageorgos_2013_Biochemistry_52_5016
PubMedID: 23795559

Title : Membrane phospholipid bilayer as a determinant of monoacylglycerol lipase kinetic profile and conformational repertoire - Nasr_2013_Protein.Sci_22_774
Author(s) : Nasr ML , Shi X , Bowman AL , Johnson M , Zvonok N , Janero DR , Vemuri VK , Wales TE , Engen JR , Makriyannis A
Ref : Protein Science , 22 :774 , 2013
Abstract : The membrane-associated serine hydrolase, monoacylglycerol lipase (MGL), is a well-recognized therapeutic target that regulates endocannabinoid signaling. Crystallographic studies, while providing structural information about static MGL states, offer no direct experimental insight into the impact of MGL's membrane association upon its structure-function landscape. We report application of phospholipid bilayer nanodiscs as biomembrane models with which to evaluate the effect of a membrane system on the catalytic properties and conformational dynamics of human MGL (hMGL). Anionic and charge-neutral phospholipid bilayer nanodiscs enhanced hMGL's kinetic properties [apparent maximum velocity (Vmax ) and substrate affinity (Km )]. Hydrogen exchange mass spectrometry (HX MS) was used as a conformational analysis method to profile experimentally the extent of hMGL-nanodisc interaction and its impact upon hMGL structure. We provide evidence that significant regions of hMGL lid-domain helix alpha4 and neighboring helix alpha6 interact with the nanodisc phospholipid bilayer, anchoring hMGL in a more open conformation to facilitate ligand access to the enzyme's substrate-binding channel. Covalent modification of membrane-associated hMGL by the irreversible carbamate inhibitor, AM6580, shielded the active site region, but did not increase solvent exposure of the lid domain, suggesting that the inactive, carbamylated enzyme remains intact and membrane associated. Molecular dynamics simulations generated conformational models congruent with the open, membrane-associated topology of active and inhibited, covalently-modified hMGL. Our data indicate that hMGL interaction with a phospholipid membrane bilayer induces regional changes in the enzyme's conformation that favor its recruiting lipophilic substrate/inhibitor from membrane stores to the active site via the lid, resulting in enhanced hMGL catalytic activity and substrate affinity.
ESTHER : Nasr_2013_Protein.Sci_22_774
PubMedSearch : Nasr_2013_Protein.Sci_22_774
PubMedID: 23553709

Title : Endocannabinoid enzyme engineering: soluble human thio-monoacylglycerol lipase (sol-S-hMGL) - Karageorgos_2012_ACS.Chem.Neurosci_3_393
Author(s) : Karageorgos I , Zvonok N , Janero DR , Vemuri VK , Shukla V , Wales TE , Engen JR , Makriyannis A
Ref : ACS Chem Neurosci , 3 :393 , 2012
Abstract : In the mammalian central nervous system, monoacylglycerol lipase (MGL) is principally responsible for inactivating the endocannabinoid signaling lipid 2-arachidonoylglycerol (2-AG) and modulates cannabinoid-1 receptor (CB1R) desensitization and signal intensity. MGL is also a drug target for diseases in which CB1R stimulation may be therapeutic. To inform the design of human MGL (hMGL) inhibitors, we have engineered a Leu(Leu(169);Leu(176))-to-Ser(Ser(169);Ser(176)) double hMGL mutant (sol-hMGL) which exhibited enhanced solubility properties, and we further mutated this variant by substituting its catalytic-triad Ser(122) with Cys (sol-S-hMGL). The hMGL variants hydrolyzed both 2-AG and a fluorogenic reporter substrate with comparable affinities. Our results suggest that the hMGL cysteine mutant maintains the same overall architecture as wild-type hMGL. The results also underscore the superior nucleophilic nature of the reactive catalytic Ser(122) residue as compared to that of Cys(122) in the sol-S-hMGL mutant and suggest that the nucleophilic character of the Cys(122) residue is not commensurately enhanced within the three dimensional architecture of hMGL. The interaction of the sol-hMGL variants with the irreversible inhibitors AM6580 and N-arachidonylmaleimide (NAM) and the reversible inhibitor AM10212 was profiled. LC/MS analysis of tryptic digests from sol-S-hMGL directly demonstrate covalent modification of this variant by NAM and AM6580, consistent with enzyme thiol alkylation and carbamoylation, respectively. These data provide insight into hMGL catalysis, the key role of the nucleophilic character of Ser(122), and the mechanisms underlying hMGL inhibition by different classes of small molecules.
ESTHER : Karageorgos_2012_ACS.Chem.Neurosci_3_393
PubMedSearch : Karageorgos_2012_ACS.Chem.Neurosci_3_393
PubMedID: 22860208
Gene_locus related to this paper: human-MGLL

Title : The novel cannabinoid CB1 receptor neutral antagonist AM4113 suppresses food intake and food-reinforced behavior but does not induce signs of nausea in rats - Sink_2008_Neuropsychopharmacology_33_946
Author(s) : Sink KS , McLaughlin PJ , Wood JA , Brown C , Fan P , Vemuri VK , Peng Y , Olszewska T , Thakur GA , Makriyannis A , Parker LA , Salamone JD
Ref : Neuropsychopharmacology , 33 :946 , 2008
Abstract : Drugs that interfere with cannabinoid CB1 transmission suppress various food-motivated behaviors, and it has been suggested that such drugs could be useful as appetite suppressants. Biochemical studies indicate that most of these drugs assessed thus far have been CB1 inverse agonists, and although they have been shown to suppress food intake, they also appear to induce nausea and malaise. The present studies were undertaken to characterize the behavioral effects of AM4113, which is a CB1 neutral antagonist, and to examine whether this drug can reduce food-reinforced behaviors and feeding on diets with varying macronutrient compositions. Biochemical data demonstrated that AM4113 binds to CB1 receptors, but does not show inverse agonist properties (ie no effects on cyclic-AMP production). In tests of spontaneous locomotion and analgesia, AM4113 reversed the effects of the CB1 agonist AM411. AM4113 suppressed food-reinforced operant responding with rats responding on fixed ratio (FR) 1 and 5 schedules of reinforcement in a dose-dependent manner, and also suppressed feeding on high-fat, high-carbohydrate, and lab chow diets. However, in the same dose range that suppressed feeding, AM4113 did not induce conditioned gaping, which is a sign of nausea and food-related malaise in rats. These results suggest that AM4113 may decrease appetite by blocking endogenous cannabinoid tone, and that this drug may be less associated with nausea than CB1 inverse agonists.
ESTHER : Sink_2008_Neuropsychopharmacology_33_946
PubMedSearch : Sink_2008_Neuropsychopharmacology_33_946
PubMedID: 17581535