Unique Pharmacological Profile Research Articles

Identification of AICP as a GluN2C-Selective N-Methyl-d-Aspartate Receptor Superagonist at the GluN1 Glycine Site.

N-methyl-d-aspartate (NMDA)-type ionotropic glutamate receptors mediate excitatory neurotransmission in the central nervous system and are critically involved in brain function. NMDA receptors are also implicated in psychiatric and neurological disorders and have received considerable attention as therapeutic targets. In this regard, administration of d-cycloserine (DCS), which is a glycine site NMDA receptor agonist, can enhance extinction of conditioned fear responses. The intriguing behavioral effects of DCS have been linked to its unique pharmacological profile among NMDA receptor subtypes (GluN1/2A-D), in which DCS is a superagonist at GluN2C-containing receptors compared with glycine and a partial agonist at GluN2B-containing receptors. Here, we identify (R)-2-amino-3-(4-(2-ethylphenyl)-1H-indole-2-carboxamido)propanoic acid (AICP) as a glycine site agonist with unique GluN2-dependent differences in agonist efficacy at recombinant NMDA receptor subtypes. AICP is a full agonist at GluN1/2A (100% response compared with glycine), a partial agonist at GluN1/2B and GluN1/2D (10% and 27%, respectively), and a highly efficacious superagonist at GluN1/2C receptors (353%). Furthermore, AICP potencies are enhanced compared with DCS with EC50 values in the low nanomolar range (1.7 nM at GluN1/2C). We show that GluN1/2C superagonism of AICP and DCS is mediated by overlapping but distinct mechanisms and that AICP selectively enhances responses from recombinant GluN1/2C receptors in the presence of physiological glycine concentrations. This functional selectivity of AICP for GluN2C-containing NMDA receptors is more pronounced compared with DCS, suggesting that AICP can be a useful tool compound for uncovering the roles of GluN2C subunits in neuronal circuit function and in the development of new therapeutic strategies.

Cariprazine Exhibits Anxiolytic and Dopamine D3 Receptor-Dependent Antidepressant Effects in the Chronic Stress Model.

BackgroundCariprazine, a D3-preferring dopamine D2/D3 receptor partial agonist, is a new antipsychotic drug recently approved in the United States for the treatment of schizophrenia and bipolar mania. We recently demonstrated that cariprazine also has significant antianhedonic-like effects in rats subjected to chronic stress; however, the exact mechanism of action for cariprazine’s antidepressant-like properties is not known. Thus, in this study we examined whether the effects of cariprazine are mediated by dopamine D3 receptors.MethodsWild-type and D3-knockout mice were exposed to chronic unpredictable stress for up to 26 days, treated daily with vehicle, imipramine (20 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.03, 0.1, 0.2, and 0.4 mg/kg), and tested in behavioral assays measuring anhedonia and anxiety-like behaviors.ResultsResults showed that cariprazine significantly attenuated chronic unpredictable stress-induced anhedonic-like behavior in wild-type mice, demonstrating potent antidepressant-like effects comparable with aripiprazole and the tricyclic antidepressant imipramine. This antianhedonic-like effect of cariprazine was not observed in D3-knockout mice, suggesting that the cariprazine antidepressant-like activity is mediated by dopamine D3 receptors. Moreover, cariprazine significantly reduced drinking latency in the novelty-induced hypophagia test in wild-type mice, further confirming its antianhedonic-like effect and showing that it also has anxiolytic-like activity.ConclusionsIn combination with previous studies, these results suggest that cariprazine has a unique pharmacological profile and distinct dopamine D3 receptor-dependent mechanism of action that may be beneficial in the treatment of schizophrenia, bipolar disorder, and major depressive disorder.

GABA-ρ receptors: distinctive functions and molecular pharmacology.

The homomeric GABA-ρ ligand-gated ion channels (also known as GABAC or GABAA -ρ receptors) are similar to heteromeric GABAA receptors in structure, function and mechanism of action. However, their distinctive pharmacological properties and distribution make them of special interest. This review focuses on GABA-ρ ion channel structure, ligand selectivity toward ρ receptors over heteromeric GABAA receptor sub-types and selectivity between different homomeric ρ sub-type receptors. Several GABA analogues show selectivity at homomeric GABA-ρ receptors over heteromeric GABAA receptors. More recently, some synthetic ligands have been found to show selectivity at receptors formed from one ρ subtype over others. The unique pharmacological profiles of these agents are discussed in this review. The classical binding site of GABA within the orthosteric site of GABA-ρ homomeric receptors is discussed in detail regarding the loops and residues that constitute the binding site. The ligand-residue interactions in this classical binding and those of mutant receptors are discussed. The structure and conformations of GABA are discussed in regard to its flexibility and molecular properties. Although the binding mode of GABA is difficult to predict, several interactions between GABA and the receptor assist in predicting its potential conformation and mode of action. The structure-activity relationships of GABA and structurally key ligands at ρ receptors are described and discussed.

RP5063, an atypical antipsychotic drug with a unique pharmacologic profile, improves declarative memory and psychosis in mouse models of schizophrenia.

Various types of atypical antipsychotic drugs (AAPDs) modestly improve the cognitive impairment associated with schizophrenia (CIAS). RP5063 is an AAPD with a diverse and unique pharmacology, including partial agonism at dopamine (DA) D2, D3, D4, serotonin (5-HT)1A, and 5-HT2A receptors (Rs), full agonism at α4β2 nicotinic acetylcholine (ACh)R (nAChR), and antagonism at 5-HT2B, 5-HT6, and 5-HT7Rs. Most atypical APDs are 5-HT2A inverse agonists. The efficacy of RP5063 in mouse models of psychosis and episodic memory were studied. RP5063 blocked acute phencyclidine (PCP)-as well as amphetamine-induced hyperactivity, indicating antipsychotic activity. Acute administration of RP5063 significantly reversed subchronic (sc)PCP-induced impairment in novel object recognition (NOR), a measure of episodic memory, but not reversal learning, a measure of executive function. Co-administration of a sub-effective dose (SED) of RP5063 with SEDs of a 5-HT7R antagonist, a 5-HT1BR antagonist, a 5-HT2AR inverse agonist, or an α4β2 nAChR agonist, restored the ability of RP5063 to ameliorate the NOR deficit in scPCP mice. Pre-treatment with a 5-HT1AR, a D4R, antagonist, but not an α4β2 nAChR antagonist, blocked the ameliorating effect of RP5063. Further, co-administration of scRP5063 prior to each dose of PCP prevented the effect of PCP to produce a deficit in NOR for one week. RP5063, given to scPCP-treated mice for one week restored NOR for one week only. Acute administration of RP5063 significantly increased cortical DA efflux, which may be critical to some of its cognitive enhancing properties. These results indicate that RP5063, by itself, or as an adjunctive treatment has a multifaceted basis for improving some cognitive deficits associated with schizophrenia.

Pharmacokinetics, tissue distribution, and excretion studies of l-isocorypalmine using ultra high performance liquid chromatography with tandem mass spectrometry.

l-Isocorypalmine is a newly identified metabolite of l-tetrahydropalmatine with a unique dual pharmacological profile as a partial dopamine receptor 1 agonist and dopamine receptor 2 antagonist properties for treating cocaine use disorder. The purpose of this study was to explore the pharmacokinetic profiles, tissue distribution, and excretion of l-isocorypalmine in Sprague-Dawley rats. A sensitive and reliable ultra high performance liquid chromatography with tandem mass spectrometry method was developed and validated for determination of l-isocorypalmine in biological samples. The biological samples were extracted by liquid-liquid extraction and separated on a Bonshell ASB C18 column (2.1 × 100 mm, 2.7 μm, Agela) with gradient mobile phase at the flow rate of 0.2 mL/min. The detection was performed by positive electrospray ionization with multiple reaction monitoring mode. Satisfactory linearity, precision, accuracy, extraction recovery, and acceptable matrix effect were achieved. The quantitative method was successfully applied to the pharmacokinetics, tissue distribution, and excretion study of l-isocorypalmine. The results showed that l-isocorypalmine was rapidly distributed, and eliminated from rat plasma and manifested linear dynamics in a dose range of 7.5-15 mg/kg. In addition, the results would be helpful for further clinical reference of l-isocorypalmine as a potential candidate drug for the treatment of cocaine addiction.

Promise of SGLT2 Inhibitors in Heart Failure: Diabetes and Beyond.

This review provides mechanistic insight in the pleiotropic effects of sodium-glucose transporter-2 (SGLT-2) inhibitors with particular interest to the pathophysiology of heart failure. The SGLT-2 inhibitor empagliflozin has recently demonstrated an unprecedented 38% reduction in cardiovascular mortality in patients with diabetes. Despite modest effects on long-term glycemic control, highly significant reductions in heart failure admissions and end-stage kidney disease were observed. SGLT-2 inhibitors are the latest approved class of glucose-lowering agents. By blocking sodium/glucose uptake in the proximal tubules of the nephron, they induce glycosuria. Treatment with SGLT-2 inhibitors in diabetes leads to a sustained ∼1% reduction in glycated hemoglobin levels, with favorable reductions in both arterial blood pressure (∼3-6mmHg) and body weight (∼2-4kg/m2). However, those effects fail to explain fully the dramatic reduction in cardiovascular mortality, heart failure readmissions, and end-stage kidney disease. The unique pharmacological profile of SGLT-2 inhibitors puts them at the crossroads of important hemodynamic, neurohumoral, metabolic, and vascular endothelial pathways influencing cardiac and renal disease. SGLT-2 inhibitors decrease proximal tubular sodium and chloride reabsorption, leading to a reset of the tubuloglomerular feedback. This induces plasma volume contraction without activation of the sympathetic nerve system, decreases harmful glomerular hyper-filtration leading to better long-term renal preservation, and improves diuretic and natriuretic responses to other diuretic agents. Moreover, SGLT-2 inhibitors might improve the efficiency of myocardial energetics by offering β-hydroxybutyrate as an attractive fuel for oxidation and increase hematocrit improving oxygen transport. Finally, decreased vascular stiffness and improved endothelial function are observed with the use of SGLT-2 inhibitors in diabetes. Those multiple nonglycemic effects reinforce SGLT-2 inhibitors as the preferred glucose-lowering drug to treat diabetic patients with heart failure. In the future, they might even be considered in heart failure or chronic kidney disease patients without diabetes.

Exploring the Structural Compliancy versus Specificity of the Estrogen Receptor Using Isomeric Three-Dimensional Ligands.

The estrogen receptors (ERs) bind with high affinity to many structurally diverse ligands by significantly distorting the contours of their ligand-binding pockets. This raises a question: To what degree is ER able to distinguish between structurally related regioisomers and enantiomers? We have explored the structural compliance and specificity of ERα with a set of ligands having a 7-oxa-bicyclo[2.2.1]hept-5-ene sulfonate core and basic side chains typical of selective ER modulators (SERMs). These ligands have two regioisomers, each of which is a racemate of enantiomers. Using orthogonal protecting groups and chiral HPLC, we isolated all 4 isomers and assigned their absolute stereochemistry by X-ray analysis. The 1S,2R,4S isomer has a 80-170-fold higher affinity for ERα than the others, and it profiles as a partial agonist/antagonist in cellular reporter gene assays and in suppressing proliferation of MCF-7 breast cancer cells with subnanomolar potency, far exceeding that of the other isomers. It is the only isomer found bound to ERα by X-ray analysis after crystallization with four-isomer mixtures of closely related analogs. Thus, despite the general compliance of this receptor for binding a large variety of ligand structures, ER demonstrates marked structural specificity and stereospecificity by selecting a single component from a mixture of structurally related isomers to drive ER-regulated cellular activity. Our findings lay the necessary groundwork for seeking unique ER-mediated pharmacological profiles by rational structural perturbations of two different types of side chains in this unprecedented class of ER ligands, which may prove useful in developing more effective endocrine therapies for breast cancer.

Risk of Extrapyramidal Adverse Events With Aripiprazole.

Aripiprazole is a unique atypical antipsychotic with partial agonist activity on the dopamine-2 (D2) receptor. This unique pharmacological profile of aripiprazole was thought to lead to a lower incidence of extrapyramidal symptoms (EPSs). However, recent case reports have alluded to an increase in the risk of EPS in aripiprazole users compared with nonusers of the drug. No epidemiologic studies to date have quantified this risk. We conducted a pharmacoepidemiologic study composed of a nested case-control study using a large health claims database (IMS Health) in the United States. In the nested case-control analysis, there were 5242 cases of EPS with 50,532 corresponding controls in the entire cohort. The odds ratio (OR) for EPS among those with any prescription of aripiprazole was 5.38 (95% confidence interval [CI], 3.03-9.57). The OR was lower among those taking 2 to 3 prescriptions (OR, 2.9; 95% CI, 1.07-7.85) but increased in those receiving greater than 4 prescriptions (OR, 8.64; 95% CI, 2.63-28.38). All risk periods were compared with those of subjects who had not used aripiprazole or other antipsychotics. For the secondary outcome of dyskinesia, the risk for aripiprazole was 8.50 (95% CI, 8.53-2.27-31.97) compared with that of nonusers. In conclusion, we found an increase in the risk of EPS and dyskinesias among users of aripiprazole.

Avanafil for the treatment of erectile dysfunction

ABSTRACTIntroduction: Erectile dysfunction (ED) affects millions of men worldwide, and the incidence of ED will continue to increase as the aging population grows. The first generation of phosphodiesterase-5 (PDE5) inhibitors, the mainstay of oral ED therapy, has revolutionized the treatment of this condition, but not without some drawbacks. Avanafil, the only United States and European Union-approved second-generation PDE5 inhibitor, is a safe and efficacious alternative to its predecessors.Areas covered: We reviewed the current and most up-to-date literature regarding Avanafil, as well as the pivotal trials that measured efficacy and tolerability. As Avanafil is still a relatively new drug, there is still a relative paucity of literature which inherently limited the search parameters. We searched the PUBMED database for articles detailing the clinical trials, chemistry, pharmacokinetics and dynamics, safety, and efficacy of the drug.Expert commentary: Avanafil’s unique pharmacologic profile both narrows and minimizes side effects while reducing the time of onset of action to half of its closest competitor, providing men who suffer with ED a return to a more spontaneous sex life.

Dexmedetomidine: its use in intensive care medicine and anaesthesia

### Key points Dexmedetomidine is a relatively new drug to the UK having been launched in October 2011 with marketing authorization for sedation of adult intensive care unit (ICU) patients only. Despite this, its unique pharmacological profile has led to its unlicensed use in a number of areas of anaesthetic and critical care practice where evidence for its efficacy is mounting. Dexmedetomidine is the S -enantiomer of the veterinary sedative medetomidine. It is a highly selective α2-adrenoceptor agonist demonstrating an α2:α1 selectivity ratio of 1620:1. This makes it eight times more selective for the α2-adrenoceptor than clonidine. Fig 1 Effects of dexmedetomidine on organ systems. ### Sedation and anxiolysis These properties are mediated via agonism of α2-adrenoceptors primarily in the locus coeruleus of the pons where it results in dose-dependent inhibition of norepinephrine release. It is postulated that this results in disinhibition of the ventrolateral preoptic nucleus which then releases inhibitory neurotransmitters. This pathway is part of the complex circuitry governing natural sleep, resulting in a quality of sedation with dexmedetomidine which more closely resembles normal physiological sleep than the more familiar GABA-ergic sedatives (propofol and the benzodiazepines). This sedation is characterized by preserved muscle tone and ventilation, by spontaneous and evoked movements, and by awakening by external stimuli. Once roused, patients are cooperative and can typically obey simple instructions. Once the external stimulus is discontinued, patients resume the previous level of sedation. Electroencephalogram studies have further confirmed that the sedative effects of dexmedetomidine mimic …

Phosphorylation state-dependent modulation of spinal glycine receptors alleviates inflammatory pain.

Diminished inhibitory neurotransmission in the superficial dorsal horn of the spinal cord is thought to contribute to chronic pain. In inflammatory pain, reductions in synaptic inhibition occur partially through prostaglandin E2- (PGE2-) and PKA-dependent phosphorylation of a specific subtype of glycine receptors (GlyRs) that contain α3 subunits. Here, we demonstrated that 2,6-di-tert-butylphenol (2,6-DTBP), a nonanesthetic propofol derivative, reverses inflammation-mediated disinhibition through a specific interaction with heteromeric αβGlyRs containing phosphorylated α3 subunits. We expressed mutant GlyRs in HEK293T cells, and electrophysiological analyses of these receptors showed that 2,6-DTBP interacted with a conserved phenylalanine residue in the membrane-associated stretch between transmembrane regions 3 and 4 of the GlyR α3 subunit. In native murine spinal cord tissue, 2,6-DTBP modulated synaptic, presumably αβ heteromeric, GlyRs only after priming with PGE2. This observation is consistent with results obtained from molecular modeling of the α-β subunit interface and suggests that in α3βGlyRs, the binding site is accessible to 2,6-DTBP only after PKA-dependent phosphorylation. In murine models of inflammatory pain, 2,6-DTBP reduced inflammatory hyperalgesia in an α3GlyR-dependent manner. Together, our data thus establish that selective potentiation of GlyR function is a promising strategy against chronic inflammatory pain and that, to our knowledge, 2,6-DTBP has a unique pharmacological profile that favors an interaction with GlyRs that have been primed by peripheral inflammation.

Spotlight on brexpiprazole and its potential in the treatment of schizophrenia and as adjunctive therapy for the treatment of major depression.

Antipsychotic agents, utilized for the treatment of a range of psychiatric disorders, differ substantially in terms of their pharmacology and adverse effect profiles. Incomplete and variable efficacy, differences in safety–tolerability, and highly heterogeneous response across individuals prompt development of new agents. Brexpiprazole is one of the two most recently introduced antipsychotic agents approved for the treatment of schizophrenia and as an adjunct for treatment of major depressive disorder. Its pharmacology, clinical trial data, and efficacy and side effects in comparison with other antipsychotic agents are discussed. Brexpiprazole is a dopamine D-2 partial agonist with potent activity at the serotonin 5HT1A and 5HT2A and noradrenergic alpha-1B and alpha-2C receptors. Placebo-controlled clinical trials in persons with schizophrenia support its efficacy in treating psychosis and preventing relapse. Short-term clinical trials also support its efficacy as an adjunct to antidepressants in treating major depressive disorder in individuals inadequately responsive to antidepressant treatment alone. Adverse effects include akathisia, gastrointestinal side effects, and moderate weight gain. The recommended oral dose of brexpiprazole is 2–4 mg/day in schizophrenia and 2–3 mg/day as adjunctive treatment in major depression. It must be titrated up to its target dose over 1–2 weeks and is effective in once-daily dosing. How brexpiprazole’s unique pharmacological profile will translate into clinically meaningful differences from other antipsychotic agents is unclear. Its place in our antipsychotic armamentarium and potential role in the treatment of schizophrenia and major depressive disorder will be determined by additional clinical data and experience.

ITI-007 in the treatment of schizophrenia: from novel pharmacology to clinical outcomes

ABSTRACTITI-007 is an investigational drug being developed for schizophrenia and other neuropsychiatric/neurodegenerative diseases. ITI-007 has a unique pharmacological profile, combining potent 5-HT2a receptor antagonism with cell-type-specific dopamine and glutamate receptor modulation, plus serotonin reuptake inhibition. At dopamine-D2 receptors, ITI-007 acts as a post-synaptic antagonist and pre-synaptic partial agonist. Additionally, ITI-007 stimulates phosphorylation of glutamatergic NMDA-NR2B receptors, downstream of dopamine-D1 receptor intracellular signaling. Based on a large, placebo and risperidone controlled, Phase-II trial, ITI-007 60 mg was shown to be effective in reducing symptoms in patients with acutely exacerbated schizophrenia. The antipsychotic efficacy of ITI-007 60 mg in this patient population was confirmed in a recently completed Phase III study. ITI-007 was associated with minimal safety risk compared to risperidone (Phase II study) or placebo (both studies) for neuromotor disturbances, prolactin changes, weight gain and metabolic abnormalities. A second 6-week, placebo and risperidone-controlled Phase-III trial in acutely exacerbated schizophrenia is ongoing.

Pharmacokinetics and In Vitro Blood-Brain Barrier Screening of the Plant-Derived Alkaloid Tryptanthrin.

The indolo[2,1-b]quinazoline alkaloid tryptanthrin was previously identified as a potent anti-inflammatory compound with a unique pharmacological profile. It is a potent inhibitor of cyclooxygenase-2, 5-lipooxygenase-catalyzed leukotriene synthesis, and nitric oxide production catalyzed by the inducible nitric oxide synthase. To characterize the pharmacokinetic properties of tryptanthrin, we performed a pilot in vivo study in male Sprague-Dawley rats (2 mg/kg bw i. v.). Moreover, the ability of tryptanthrin to cross the blood-brain barrier was evaluated in three in vitro human and animal blood-brain barrier models. Bioanalytical UPLC-MS/MS methods used were validated according to current international guidelines. A half-life of 40.63 ± 6.66 min and a clearance of 1.00 ± 0.36 L/h/kg were found in the in vivo pharmacokinetic study. In vitro data obtained with the two primary animal blood-brain barrier models showed a good correlation with an immortalized human monoculture blood-brain barrier model (hBMEC cell line), and were indicative of a high blood-brain barrier permeation potential of tryptanthrin. These findings were corroborated by the in silico prediction of blood-brain barrier penetration. P-glycoprotein interaction of tryptanthrin was assessed by calculation of the efflux ratio in bidirectional permeability assays. An efflux ratio below 2 indicated that tryptanthrin is not subjected to active efflux.

From biased signalling to polypharmacology: unlocking unique intracellular signalling using pepducins.

For over a decade, pepducins have been utilized to develop unique pharmacological profiles that have been particularly challenging for traditional drug discovery methods. It is becoming increasingly clear that these cell-penetrating lipopeptides can access receptor conformations that are currently not accessible through orthosteric targeting. This review addresses the emerging concepts in the development of pepducins including the elicitation of biased signalling, pepducin polypharmacology and recent insight into their mechanism of action.

Abuse Liability and Anti‐Addiction Potential of the Atypical Mu Opioid Receptor Agonist IBNtxA

OBJECTIVEIBNtxA is a novel μ opioid receptor (MOR) agonist, structurally related to the classical MOR antagonist naltrexone, that preferentially signals through truncated MOR splice variants. This unique pharmacological profile produces potent analgesia with reduced side effects, including no conditioned place preference (CPP) when tested at a single dose. The purpose of this study is to 1) evaluate a range of IBNtxA doses to more fully assess its abuse liability and 2) determine the effects of IBNtxA on morphine CPP expression and reinstatement of morphine CPP.METHODSIBNtxA was synthesized and compared to morphine in standard CPP expression assays. Following morphine CPP training, IBNtxA was tested for its effects in inducing CPP reinstatement on its own or attenuating morphine‐primed reinstatement.RESULTS and CONCLUSIONSIBNtxA is an intriguing preclinical drug that opens the door to new MOR splice variant‐selective pharmacotherapeutics with effective analgesic properties but reduced side effects. IBNtxA may have utility as an adjunct therapy in agonist replacement strategies (e.g., methadone). Current collaborative efforts are aimed at developing novel analogues of IBNtxA for further analysis and understanding ligand‐receptor interactions across MOR splice variants using molecular modeling.Support or Funding InformationRowan University Seed Fund; travel support from Dean of College of Science and Mathematics and the Rowan University Assistant Professor and Instructor Travel Fund.

Dual Alpha2C/5HT1A Receptor Agonist Allyphenyline Induces Gastroprotection and Inhibits Fundic and Colonic Contractility.

Allyphenyline, a novel α2-adrenoceptor (AR) ligand, has been shown to selectively activate α2C-adrenoceptors (AR) and 5HT1A receptors, but also to behave as a neutral antagonist of α2A-ARs. We exploited this unique pharmacological profile to analyze the role of α2C-ARs and 5HT1A receptors in the regulation of gastric mucosal integrity and gastrointestinal motility. Gastric injury was induced by acidified ethanol in Wistar rats. Mucosal catalase and superoxide dismutase levels were measured by assay kits. The effect of allyphenyline on electrical field stimulation (EFS)-induced fundic and colonic contractions was determined in C57BL/6 mice. Intracerebroventricularly injected allyphenyline (3 and 15nmol/rat) dose dependently inhibited the development of mucosal damage, which was antagonized by ARC 239 (α2B/C-AR and 5HT1A receptor antagonist), (S)-WAY 100135 (selective 5HT1A receptor antagonist), and JP-1302 (selective α2C-AR antagonist). This protection was accompanied by significant elevation of mucosal catalase and superoxide dismutase levels. Allyphenyline (10(-9)-10(-5) M) also inhibited EFS-induced fundic contractions, which was antagonized by ARC 239 and (S)-WAY 100135, but not by JP-1302. Similar inhibition was observed in the colon; however, in this case only ARC 239 reduced this effect, while neither selective inhibition of α2C-ARs and 5HT1A receptors nor genetic deletion of α2A- and α2B-ARs influenced it. Activation of both central α2C-ARs and 5HT1A receptors contributes to the gastroprotective action of allyphenyline in rats. Its inhibitory effect on fundic contractions is mediated by 5HT1A receptors, but neither α2-ARs nor 5HT1A receptors take part in its inhibitory effect on colonic contractility in mice.

Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring.

Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults. It accounts for approximately 15% of newly diagnosed cases of leukemia in adults. CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson gene (ABL1) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL1 fusion oncogene, which in turn translates into a BCR-ABL oncoprotein. Frontline therapy: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib are approved by the United States Food and Drug Administration for first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with 2nd generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined. Salvage therapy: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Although second and third generation TKIs are potent and selective TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient and disease characteristics, such as patients' comorbidities, disease stage, and BCR-ABL1 mutational status. Patients who develop the T315I "gatekeeper" mutation display resistance to all currently available TKIs except ponatinib. Allogeneic stem cell transplantation remains an important therapeutic option for patients with CML-CP who have failed at least two TKIs, and for all patients in advanced phase disease.

Levo-tetrahydropalmatine, a natural, mixed dopamine receptor antagonist, inhibits methamphetamine self-administration and methamphetamine-induced reinstatement

Despite the high prevalence of methamphetamine (METH) use, no FDA-approved pharmacological treatment is currently available for individuals with a METH addiction. Levo-tetrahydropalmatine (l-THP) is an alkaloid substance derived from corydalis and stephania that has been used in traditional Asian medicine for its analgesic, sedative and hypnotic properties. Previous pharmacological studies of l-THP indicated that it not only binds to D1 and D2 receptors but also has a low affinity for D3 receptors and may function as an antagonist. The unique pharmacological profile of l-THP suggests that it may have potential therapeutic effects on drug addiction; however, the effects of l-THP in individuals with METH addictions are largely unknown. In this study, we investigated the effects of l-THP on METH self-administration and METH-induced reinstatement. In our experiments, l-THP (1.25, 2.50 and 5.00mg/kg, i.p.) decreased METH self-administration under the fixed-ratio 1 schedule. l-THP (2.50 and 5.00mg/kg, i.p) also prevented the METH-induced reinstatement of METH-seeking behaviors. Interestingly, l-THP (1.25 and 2.50mg/kg, i.p) did not affect locomotor activity following METH injection (1mg/kg) suggesting that the observed effects of l-THP (2.50mg/kg) on METH-induced reinstatement were not due to motor impairments. Thus, l-THP (a natural, mixed dopamine (DA) receptor antagonist) attenuates METH self-administration and METH-induced reinstatement.

A Review of the Literature of Mirtazapine in Co-Occurring Depression and an Alcohol Use Disorder.

Prior medication studies involving individuals with major depression in combination with an alcohol use disorder (MDD/AUD) have mainly focused on SSRI and tricyclic antidepressants, with generally ineffective results. Consequently, effective treatments for that common comorbid condition remain elusive. Mirtazapine is an antidepressant medicine with a unique pharmacological profile, whose effectiveness for treating non-comorbid depression reportedly may exceed that of SSRIs. We now review the published literature regarding the tolerability and efficacy of mirtazapine for the treatment of the depression and the pathological alcohol ingestion of individuals with co-occurring MDD/AUD, including a review of four of our own small studies and two studies conducted outside the United States. The findings of these studies suggest that mirtazapine is well tolerated among persons with comorbid MDD/AUD. Results also provide some evidence of efficacy for mirtazapine for decreasing the level of depression of persons with co-occurring MDD/AUD, and suggest that decreases in depression may occur relatively quickly after starting treatment, but provide no evidence of effectiveness for decreasing the level of alcohol ingestion. Large-scale double-blind, placebo-controlled studies are warranted to further clarify the tolerability and efficacy of mirtazapine among individuals with MDD/AUD.