Receptors In Central Nervous System Research Articles

Posture and vision: How different distances of viewing target affect postural stability and plantar pressure parameters in healthy population

BackgroundPostural stability is maintained by the Postural Control System (PCS), consisting of anatomical structures of Central Nervous System and peripheral receptors, interacting with each other, in order to keep whole-body balance by modulating the myofascial chains against gravity. The vision is one of the most important peripheral receptors for postural control. Previous studies analyzed the changes of body sway during viewing nearby (VNT) and distant (VDT) targets in healthy population without considering the feet adaptations related to the body weight distribution. Aim of this study was to investigate how different distances of viewing target affect the variability of postural stability and plantar pressure parameters in healthy subjects. Methods31 stabilometric and plantar pressure parameters were acquired in 20 young healthy subjects by baropodometry performed in bipedal standing during VNT and VDT (0.70 m and 3 m from the heels, respectively). Variability and statistical differences between VDT and VNT were implemented. ResultsResults showed the highest repeatability for plantar pressure parameters, a slightly high for CP speed and a lowest for CoPsa and Length Surface Function during both VNT and VDT. Moreover, a significant increase of load percentage on left-foot and right-Forefoot, of mean and maximum pressures on left-Forefoot, of CoPsa and CPspeed and a decrease of LSF were found during VDT. DiscussionThis study revealed how a greater distance of viewing target affects body-weight distribution and increases body oscillations. These findings highlighted the importance of visual target distance for the correct interpretation of postural stability and plantar pressure parameters, and the need to standardize target distance during stabilometric exam.

Development of Novel Tools for Dissection of Central Versus Peripheral Dopamine D2-Like Receptor Signaling in Dysglycemia.

Dopamine (DA) D2-like receptors in both the central nervous system (CNS) and the periphery are key modulators of metabolism. Moreover, disruption of D2-like receptor signaling is implicated in dysglycemia. Yet, the respective metabolic contributions of CNS versus peripheral D2-like receptors including D2 (D2R) and D3 (D3R) receptors remain poorly understood. To address this, we developed new pharmacological tools, D2-like receptor agonists with diminished and delayed blood-brain barrier capability, to selectively manipulate D2R/D3R signaling in the periphery. We designated bromocriptine methiodide (BrMeI), a quaternary methiodide analogue of D2R/D3R agonist and diabetes drug bromocriptine, as our lead compound based on preservation of D2R/D3R binding and functional efficacy. We then used BrMeI and unmodified bromocriptine to dissect relative contributions of CNS versus peripheral D2R/D3R signaling in treating dysglycemia. Systemic administration of bromocriptine, with unrestricted access to CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, dysglycemic mice in vivo. In contrast, metabolic improvements were attenuated when access to bromocriptine was restricted either to the CNS through intracerebroventricular administration or delayed access to the CNS via BrMeI. Our findings demonstrate that the coordinated actions of both CNS and peripheral D2-like receptors are required for correcting dysglycemia. Ultimately, the development of a first-generation of drugs designed to selectively target the periphery provides a blueprint for dissecting mechanisms of central versus peripheral DA signaling and paves the way for novel strategies to treat dysglycemia.

Cannabinoid CB2 receptor ligands disrupt the sequential regulation of p-MEK1/2 to p-ERK1/2 in mouse brain cortex

Aim: The sequential phosphorylation of mitogen-activated protein (MAP) kinases MEK-ERK is the most relevant cellular signaling pathway. This study quantified the parallel in vivo regulation of brain phosphorylation-MEK1/2 (p-MEK1/2) to p-ERK1/2 by mechanistically different cannabinoid 2 (CB2) receptor ligands, i.e., direct (and endogenous) agonists and inverse agonists. Methods: Groups of Swiss albino CD1 IGS male adult mice were treated (i.p.) with the CB2 agonist JWH133 (1 mg/kg and 3 mg/kg, 1 h, n = 8) or the CB2 inverse agonist/antagonist AM630 (0.3 mg/kg and 1 mg/kg, 1.5 h, n = 8–9), and 0.9% NaCl (2 mL/kg, 1 h, n = 4–10) as vehicle control. Transgenic male mice overexpressing cortical CB2 receptors [messenger RNA (mRNA) and protein] on a Swiss ICR congenic background (CB2xP) and the corresponding littermates age-matched wild-type (WT) controls were used. Protein forms (total MEK and ERK p-kinases) were resolved by electrophoresis [sodium dodecyl-sulfate polyacrylamide gel electrophoresis (SDS-PAGE) minigels] followed by immunoblotting standard procedures. Results: The selective CB2 agonist JWH133 (1 mg/kg and 3 mg/kg, i.p., 1 h) modestly decreased MEK (17%, n = 8) and upregulated ERK (25%, n = 8) activities. The endogenous CB2 agonists (acting on promoted overexpressed receptors) decreased MEK (44%, n = 9) and upregulated ERK (67%, n = 10) activities. The inverse agonist/antagonist AM630 (0.3 mg/kg and 1 mg/kg, i.p., 1.5 h) increases MEK activity (27%, n = 8) without significantly altering that of ERK (5%, n = 9). Conclusions: Acute treatments of mice with mechanistically different CB2 receptor ligands (i.e., direct agonists, endogenous agonists, and inverse agonists) resulted in disruption of MEK (p-MEK/total-MEK ratio) to ERK (p-ERK/total-ERK ratio) signals in the brain cortex. This striking disruption of MEK to ERK parallel regulation in the cannabinoid CB2 receptor system in the brain could be relevant to the postulated role of CB2 receptors in various central nervous system (CNS) diseases.

Reverse Docking Approach Reveals the Negative Effect of Caffeine Toxicity on Glutamate GluR2 Receptor

In the past decade, the consumption of caffeine has increased exponentially throughout the world. Caffeine is now not only limits to coffee but is present in several desserts and other beverages as well. Caffeine is a psychostimulant that helps in improving your performance but its excessive consumption can also affect the cognitive functions of the Central Nervous System (CNS) negatively. The present research is an attempt to understand the mechanism of caffeine action in blocking central nervous system receptors thereby affecting brain function adversely. The reverse docking approach of computational biology has been implied to visualize the interaction of several neurotransmitter receptors with caffeine. Reverse molecular docking is an approach for determining the effect of a ligand on a range of receptors. The binding energy of the receptors with caffeine is considered for determining the best receptor-ligand complex. A list of 7 different neurotransmitters was identified through a literature study and taken into consideration in the current research. The molecular interaction of the human neuro-receptors was seen with caffeine using AutoDock4.0 to study the impact of caffeine on several biological processes of the human brain. The molecular docking approach identifies glutamate gluR2 receptor to be adversely affected by caffeine toxicity thereby affecting the neurotransmission process in the human nervous system.

Activity Models of Key GPCR Families in the Central Nervous System: A Tool for Many Purposes.

G protein-coupled receptors (GPCRs) are targets of many drugs, of which ∼25% are indicated for central nervous system (CNS) disorders. Drug promiscuity affects their efficacy and safety profiles. Predicting the polypharmacology profile of compounds against GPCRs can thus provide a basis for producing more precise therapeutics by considering the targets and the anti-targets in that family of closely related proteins. We provide a tool for predicting the polypharmacology of compounds within prominent GPCR families in the CNS: serotonin, dopamine, histamine, muscarinic, opioid, and cannabinoid receptors. Our in-house algorithm, "iterative stochastic elimination" (ISE), produces high-quality ligand-based models for agonism and antagonism at 31 GPCRs. The ISE models correctly predict 68% of CNS drug-GPCR interactions, while the "similarity ensemble approach" predicts only 33%. The activity models correctly predict 56% of reported activities of DrugBank molecules for these CNS receptors. We conclude that the combination of interactions and activity profiles generated by screening through our models form the basis for subsequent designing and discovering novel therapeutics, either single, multitargeting, or repurposed.

The potential role of astroglial GABAA receptors in autoimmune encephalitis associated with GABAA receptor antibodies and seizures.

The γ-aminobutyric acid (GABA) is the main inhibitory transmitter in the central nervous system and GABA receptors mediate the inhibitory synaptic transmission. GABA binding to neuronal GABAA R leads to a rapid hyperpolarization and a higher excitation threshold due to an increase in membrane Cl- permeability. The synaptic GABAA R is mostly composed of two α(1-3), two β, and one γ subunit with the most abundant configuration α1β2γ2. Recently, antibodies (Abs) against α1, β3, and γ2 subunits of GABAA R were detected in a severe form of autoimmune encephalitis with refractory seizures, status epilepticus, and multifocal brain lesions, affecting gray and white matter. Experimental studies confirmed multiple mechanisms and direct functional effects of GABAA R Abs on neurons with decreased GABAergic synaptic transmission and increased neuronal excitability. The expression of GABAA R on astrocytes is well established. However, extensive studies about the effects of autoimmune GABAA R Abs on astrocytic GABAA R are missing. We hypothesize that GABAA R Abs may lead additionally to blocking astrocytic GABAA Rs with impaired Ca2+ homeostasis/spreading, astrocytic Cl- imbalance, dysfunction of astrocyte-mediated gliotransmission (e.g., decreased adenosine levels) and accumulation of excitatory neurotransmission, all this contributing to seizures, variable clinical/MRI presentations, and severity. The most abundant expressed GABAA R subunits in rodent astrocytes are α1, α2, β1, β3, and γ1 localized in both white and gray matter. Data about GABAA R subunits in human astrocytes are even more limited, comprising α2, β1, and γ1. Overlapping binding of GABAA R Abs to neuronal and astroglial receptors is still possible. In vitro and in vivo animal models can be helpful to test the effects of GABAA R Abs on glia. This is from an epileptological point of view relevant because of the increasing evidence, confirming the glial involvement in the pathogenesis of epilepsy. Taken together, autoimmune disorders are complex and multiple mechanisms including glia could contribute to the pathogenesis of GABAA R encephalitis with seizures.

Depression and Its Phytopharmacotherapy-A Narrative Review.

Depression is a mental health disorder that develops as a result of complex psycho-neuro-immuno-endocrinological disturbances. This disease presents with mood disturbances, persistent sadness, loss of interest and impaired cognition, which causes distress to the patient and significantly affects the ability to function and have a satisfying family, social and professional life. Depression requires comprehensive management, including pharmacological treatment. Because pharmacotherapy of depression is a long-term process associated with the risk of numerous adverse drug effects, much attention is paid to alternative therapy methods, including phytopharmacotherapy, especially in treating mild or moderate depression. Preclinical studies and previous clinical studies confirm the antidepressant activity of active compounds in plants, such as St. John's wort, saffron crocus, lemon balm and lavender, or less known in European ethnopharmacology, roseroot, ginkgo, Korean ginseng, borage, brahmi, mimosa tree and magnolia bark. The active compounds in these plants exert antidepressive effects in similar mechanisms to those found in synthetic antidepressants. The description of phytopharmacodynamics includes inhibiting monoamine reuptake and monoamine oxidase activity and complex, agonistic or antagonistic effects on multiple central nervous system (CNS) receptors. Moreover, it is noteworthy that the anti-inflammatory effect is also important to the antidepressant activity of the plants mentioned above in light of the hypothesis that immunological disorders of the CNS are a significant pathogenetic factor of depression. This narrative review results from a traditional, non-systematic literature review. It briefly discusses the pathophysiology, symptomatology and treatment of depression, with a particular focus on the role of phytopharmacology in its treatment. It provides the mechanisms of action revealed in experimental studies of active ingredients isolated from herbal antidepressants and presents the results of selected clinical studies confirming their antidepressant effectiveness.

Synthesis, structure, in vitro pharmacology, and in vivo activity of trans-3,4-dichloro-N-[[1-(dimethylamino)-4-phenylcyclohexyl]methyl]-benzamide (AP01; 4-phenyl-AH-7921), a novel mixed μ-/κ-opioid.

Analogs of non-fentanyl novel synthetic opioids (NSO) with modifications that fall outside of established structure-activity relationships (SARs) for that class of drugs create the question whether or not it should be considered an analog, as defined by 21 U.S.C. §802(32)(A), which is important for its inclusion in the US system of drug scheduling. AH-7921 is a US Schedule I drug and an example of the 1-benzamidomethyl-1-cyclohexyldialkylamine class of NSO. The SARs regarding substitution of the central cyclohexyl ring have not been well characterized in the literature. Therefore, in order to expand the SAR surrounding AH-7921 analogs, trans-3,4-dichloro-N-[[1-(dimethylamino)-4-phenylcyclohexyl]methyl]-benzamide (AP01; 4-phenyl-AH-7921) has been synthesized, analytically characterized, and tested in vitro and in vivo pharmacologically. Using methods described in the original patents for this class of NSO, it was found that the single trans geometric isomer was obtained. The proton nuclear magnetic resonance, mass spectrum, infrared spectrum, and Raman spectrum are reported along with the melting point of the hydrochloride salt. In vitro binding to a battery of 43 central nervous system receptors showed it to be a high-affinity μ-opioid receptor (MOR) and κ-opioid receptor (KOR) ligand (60 nM and 34 nM, respectively). AP01 also had a 4nM affinity for the serotonin transporter (SERT), which is a higher level of potency at this receptor than most other opioids. In rats, it exhibited antinociception in the acetic acid writhing test. Therefore, the 4-phenyl modification results in an active NSO, but carries with it potential toxicities beyond those expected for currently approved opioid drugs.

Structural basis for the allosteric modulation of GABAA receptors by neurosteroids.

GABAA receptor, a pentameric ligand-gated ion channel (pLGIC) is the major inhibitory receptor in the human central nervous system. GABAA receptors could be assembled from 19 different subunits to form several subtypes. Both α1β2γ2 and α1β3γ2 subtypes constitute around 60% of all GABAA receptors in humans. GABAA receptor dysfunction is implicated in several neuropsychiatric abnormalities, including anxiety, depression, and epilepsy. Neurosteroids have been shown to modulate GABAA receptors through transmembrane sites, majorly through those located at the β/α interface. Recent FDA approval of allopregnanolone and ganaxolone for post-partum depression and epilepsy, respectively, demonstrate the increasingly important therapeutic role of neurosteroids. However, how subtle differences in their structures affect their subtype-specific binding and subsequent activation mechanism remain poorly understood. In this study, we examined the structural basis for allosteric modulation of α1β2γ2 and α1β3γ2 subtypes of the GABAA receptor by endogenous (allopregnanolone, THDOC) and synthetic (ganaxolone) neurosteroids. Using classical and enhanced simulation techniques, we studied the membrane partitioning characteristics and elucidated the access pathways of the neurosteroids to the receptor. Furthermore, unbiased simulations of closed and desensitized GABAA receptors in the presence and absence of neurosteroids were investigated for a total simulation time of 16 μs. We monitored the dynamic structural observables including global twisting, tilting, pore geometry, network interactions between orthosteric and allosteric sites, and orientations of important loops. We observed differential polar and hydrophobic interactions of the neurosteroids within the binding site, supported by membrane lipids. Our in-silico analyses provide useful insights into the structural basis for positive allosteric modulation of GABAA receptors, which will guide the design of new allosteric modulators of GABAA receptors.

GABAA and serotonergic receptors participation in anxiolytic effect of chalcones in adult zebrafish

The prevalence of anxiety is a significant public health problem, being the 24th leading cause of disability in individuals affected by this disorder. In this context, chalcones, a flavonoid subclass obtained from natural or synthetic sources, interact with central nervous system (CNS) receptors at the same binding site as benzodiazepines, the primary drugs used in the treatment of anxiety. Thus, our study investigates the anxiolytic effect of synthetic chalcones derived from the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone isolated from Croton anisodontus Müll.Arg. in modulating anxiolytic activity via GABAergic and serotoninergic neurotransmission in an adult zebrafish model. Chalcones 1 and 2 were non-toxic to adult zebrafish and showed anxiolytic activity via GABAA receptors. Chalcone 2 also had its anxiolytic action reversed by the antagonist granisetron, indicating the participation of serotonergic receptors 5HTR3A/3B in the anxiolytic effect. In addition, molecular docking results showed that chalcones have a higher affinity for the GABAA receptor than DZP and binding in the same region of the DZP binding site, indicating a similar effect to the drug. Furthermore, the interaction of chalcones with GABAA and 5-HT3A receptors demonstrates the anxiolytic effect potential of these molecules. Communicated by Ramaswamy H. Sarma

Current perspectives on benzoflavone analogues with potent biological activities: A review

Medicinal chemistry investigators have isolated and synthesized benzoflavone analogues with diverse bioactivities including enzyme inhibitory activity, central nervous system (CNS) activity, anti-inflammatory activity, anti-microorganism activity, hypoglycemic activity, and receptor modulating potential. SAR (Structure-Activity Relationship) studies have been conducted extensively and plenty of benzoflavone analogues have been prepared for potential targets. Herein, we review the pharmacology properties and SAR for benzoflavone analogues, and provide a brief summarization of synthetic strategies, wishing to give perspective on the research and development of benzoflavone derivatives.

Metabolic detoxification and ace-1 target site mutations associated with acetamiprid resistance in Aedes aegypti L.

Despite the continuous use of chemical interventions, Aedes-borne diseases remain on the rise. Neonicotinoids are new, safer, and relatively effective pharmacological interventions against mosquitoes. Neonicotinoids interact with the postsynaptic nicotinic acetylcholine receptors (nAChRs) of the insect central nervous system, but the absence of nAChR polymorphism in resistant phenotypes makes their involvement in neonicotinoid resistance uncertain. Thus, an investigation was carried out to understand the role of metabolic detoxification and target site insensitivity in imparting acetamiprid resistance in Aedes aegypti larvae. Studies were conducted on the parent susceptible strain (PS), acetamiprid-larval selected strain for five generations (ACSF-5; 8.83-fold resistance) and 10 generations (ACSF-10; 19.74-fold resistance) of Ae. aegypti. The larval selection raised α-esterase and β-esterase activities by 1.32-fold and 1.34-fold, respectively, in ACSF-10 as compared to PS, while the corresponding glutathione-S-transferase and acetylcholinesterase activity increased by 22.5 and 2%. The ace-1 gene in PS and ACSF-10 showed four mismatches in the 1312—1511 bp region due to mutations in the Y455C codon (tyrosine to cysteine) at the 1367th position (TAC→TGC); I457V codon (isoleucine to valine) at 1372 bp and 1374 bp (ATA→GTG); and R494M codon (arginine to methionine) at 1484 bp (AGG→ATG). The R494M mutation was the novel and dominant type, observed in 70% ACSF-10 population, and has not been reported so far. The studies evidenced the combination of metabolic detoxification and target site mutation in imparting acetamiprid resistance in Ae. aegypti.

1299-P: Novel Tools to Dissect the Metabolic Roles of Central and Peripheral Dopamine D2-Like Receptors

Dopamine (DA) D2-like receptors are key physiological modulators of metabolism under healthy and disease states. While D2-like receptors are expressed both in the central nervous system (CNS) and within the periphery, the respective metabolic roles of CNS and peripheral D2-like receptors remain poorly understood. Therefore, to disentangle these CNS versus peripheral contributions, we synthesized a series of new peripherally-limited D2-like receptor agonists. We selected bromocriptine methiodide, a quaternary methiodide (MeI) analog of bromocriptine as our lead compound based on preservation of its binding and functional efficacy at D2-like receptors and its diminished blood brain barrier permeability. Systemic administration of bromocriptine, with unrestricted access to both CNS and peripheral targets, significantly improved both insulin sensitivity and glucose tolerance in obese, insulin-resistant mice in vivo. In contrast, metabolic improvements were abolished when bromocriptine’s access was restricted either to the CNS through intracerebroventricular administration or to the periphery via the peripherally-limited bromocriptine MeI. Our findings therefore suggest that the coordinated actions of both CNS and peripheral D2-like receptors are required for bromocriptine’s therapeutic efficacy in correcting dysglycemia. Overall, bromocriptine MeI may serve as a useful new tool to further dissect these mechanisms of peripheral DA signaling. Disclosure M.P. Ellenberger: None. Z. Farino: None. J. Mantilla-Rivas: None. B. Slusher: None. Funding Department of Defense (PR141292) , National Institutes of Health (R01DK124219)

Dealing with Posttraumatic Nightmares

IntroductionPosttraumatic nightmares are one of the most frequent symptoms in posttraumatic stress disorder. Prevalence can be up to 96%. These nightmares evoke the experienced traumatic event, causing a negative impact. Besides, they are and independent risk for suicide. There are different pharmacological and non-pharmacological options for PTN, despite is no optimal treatment.ObjectivesTo analyse the different treatment options for PTN.MethodsThis was a narrative literature review.ResultsThe two main treatments for PTN nowadays are the Imagery Rehearsal Therapy (IRT) and prazosin. IRT is a cognitive-behavioral intervention, that helps the patient to change the content of the nightmare to a “happier ending”. Prazosin is an alpha-adrenergic receptor antagonist that blocks the stress response in the central nervous system receptors. Although it was a promising drug, significant differences compared to placebo have not been found. There is growing data that suggests nabilone, a synthetic cannabinoid, could be helpful in PTN treatment. A clinical trial made in Canada revealed that 72% of patients experienced a complete disappearance or at least an important reduction of PTN.ConclusionsPTN is a very common and distressing symptom in patients presenting PTSD. Nevertheless, there is no treatment with enough evidence for this pathology. On this account, it is fundamental to do more research in order to find and suitable treatment that can improve the quality of life of these patients.DisclosureNo significant relationships.

The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study

Arginine vasopressin (AVP) is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, permits the experimental validation of vasopressin's role in the regulation of anxiety and fear in humans. Here, we examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to potential threat). Healthy volunteers received both SRX246 and placebo in a randomized, double-blind, counter-balanced order separated by a 5-7-day wash-out period. Threat consisted of unpleasant electric shocks. The "NPU" threat test probed startle reactivity during predictable threat (i.e., fear-potentiated startle) and unpredictable threat (i.e., anxiety-potentiated startle). As predicted, SRX246 decreased anxiety-potentiated startle independent of fear-potentiated startle. As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target.

Bromodomain‐Containing Protein 4 (BRD4) Inhibitors as Emerging Therapeutics for Opioid Use Disorder

Aims Bromodomain-containing protein 4 (BRD4) is a member of the bromodomain and extra-terminal domain-containing (BET) family of chromatin “reader” proteins. Small molecule BET inhibitors have been developed within the context of cancer and inflammation pathologies, and more recently are of interest for central nervous system (CNS) disorders, including opioid use disorder (OUD). BRD4 has two bromodomains (BDs) that recognize specific post-translational histone variants to control downstream transcriptional outcomes. The protein-protein interaction between BRD4 and lysine residues of histones is driven through the two highly conserved N-terminal bromodomains BD1 and BD2. The aim of the present study is to pharmacologically characterize BRD4-BD1-specific inhibitors to facilitate investigations into the role of BRD4 mechanisms in preclinical models of opioid use disorder. Methods Selected potent BRD4 inhibitors were synthesized and scaled up for analyses of in vitro and in vivo drug metabolism and pharmacokinetics (DMPK), blood-brain barrier (BBB) penetration, and pharmacological profiles against a panel of CNS receptors, channels and transporters via the Psychoactive Drug Screening Program (PDSP). Based on initial profiles, we further evaluated one compound for in vivo efficacy in male Sprague-Dawley rats trained to stability on intravenous oxycodone self-administration (0.1 mg/kg/infusion). Results ZL0513, ZL0516, ZL0742, and ZL0969 exhibit selectivity for BRD4-BD1 over other BD proteins and are the subject of ongoing profiling. To date, ZL0513, ZL0516, and ZL0969 exhibit excellent in vitro DMPK profiles, including bioavailability greater than 35%, aqueous solubility, metabolic stability, and weak inhibition of CYP450 enzymes. ZL0987 (HCl salt form of ZL0516) exhibited a brain/plasma ratio (intravenous, 1 hr) of 0.08 which was improved to 0.62 for ZL0969. However, ZL0516 exhibited a cleaner PDSP profile than did ZL0969. ZL0742 exhibited a good in vivo DMPK, however its penetration of the BBB was suboptimal. Additional backup molecules ZL0513 and ZL0742 are undergoing further DMPK, BBB, and PDSP screening. Based upon our initial profiling of ZL0987, we assessed its efficacy in vivo and found that ZL0987 at the dose of 10 mg/kg suppressed oxycodone intake (p<0.05) which was sustained across the entire 180-minute self-administration session. Conclusion We have characterized several BRD4-BD1 selective inhibitors with compelling profiles of drug-like properties. Our initial in vivo data revealed that ZL0987 elicited sustained suppression of oxycodone self-administration. The development and characterization of specific BRD4 inhibitors will allow exploration of BRD4 mechanisms in preclinical models of opioid use and validate the BRD4 as a novel drug target for the development of epigenetic therapeutics for OUD.

Recent advances in the biology of bombesin-like peptides and their receptors.

The current review aims to update the important findings about molecular and cellular biology of mammalian bombesin-like peptides (BLPs) and their receptors. Recent identification of synaptic communication between gastrin-releasing peptide (GRP) neurons and GRP receptor (GRPR) neurons in spinal itch relay provides us novel insights into physiology of itch sensation. Neuromedin B (NMB) neurons were found to form connections with subcortical areas associated with arousal, hippocampal theta oscillation, and premotor processing and project to multiple downstream stations to regulate locomotion and hippocampal theta power. In addition to researches regarding the roles of BLPs and their receptors in central nervous system, recent findings reveal that NMB receptor is expressed on helminth-induced type 2 innate lymphoid cells and is regulated by basophils, suggesting an important function of NMB in helminth-induced immune responses. Bombesin transactivates epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and HER3 receptors on human nonsmall-cell lung cancer (NSCLC) cells and elicits downstream signaling cascades and induces formation of both human epidermal growthfactor receptor 3 (HER3)/EGFR and HER3/HER2 heterodimers. Several high-affinity ligands for bombesin receptors were characterized, providing useful tools in investigation of biological roles of those peptides and their receptors. The most exciting findings of BLPs and their receptors in the past year come from studies in central nervous system. In addition, more researches are still underway to probe the molecular mechanisms of those peptides in peripheral tissues and characterize novel synthetic ligands with high affinity for mammalian bombesin receptors.

Isolation and Pharmacological Characterization of Six Opioidergic Picralima nitida Alkaloids.

The seeds of the akuamma tree (Picralima nitida) have been used as a traditional treatment for pain and fever. Previous studies have attributed these effects to a series of indole alkaloids found within the seed extracts; however, these pharmacological studies were significantly limited in scope. Herein, an isolation protocol employing pH-zone-refining countercurrent chromatography was developed to provide six of the akuamma alkaloids in high purity and quantities sufficient for more extensive biological evaluation. Five of these alkaloids, akuammine (1), pseudo-akuammigine (3), akuammicine (4), akuammiline (5), and picraline (6), were evaluated against a panel of >40 central nervous system receptors to identify that their primary targets are the opioid receptors. Detailed in vitro investigations revealed 4 to be a potent kappa opioid receptor agonist, and three alkaloids (1-3) were shown to have micromolar activity at the mu opioid receptor. The mu opioid receptor agonists were further evaluated for analgesic properties but demonstrated limited efficacy in assays of thermal nociception. These findings contradict previous reports of the antinociceptive properties of the P. nitida alkaloids and the traditional use of akuamma seeds as analgesics. Nevertheless, their opioid-preferring activity does suggest the akuamma alkaloids provide distinct scaffolds from which novel opioids with unique pharmacologic properties and therapeutic utility can be developed.

A Review of Antipsychotics and Priapism.

Pharmacologically induced priapism is now the most common cause of priapism, with approximately 50% of drug-related priapism being attributed to antipsychotic usage. The majority of pharmacologic priapism is believed to result in ischemic priapism (low flow), which may lead to irreversible complications, such as erectile dysfunction. It is imperative that prescribing physicians be aware of potentially inciting medications. To identify medications, specifically antipsychotics, associated with priapism and prolonged erections and understand the rates and treatment of these side effects. A PubMed search of all articles available on the database relating to priapism, prolonged erections, and antipsychotics was performed. Various typical and atypical antipsychotic drugs (APDs) have been implicated in pharmacologically induced priapism. In addition to dopaminergic and serotoninergic receptors, APDs have affinities for a wide array of other receptors in the central nervous system, including histaminergic, noradrenergic, and cholinergic receptors. Although the exact mechanism is unknown, the most commonly proposed mechanism of priapism associated with APDs is α-adrenergic blockade in the corpora cavernosa of the penis. Priapism appears in only a small fraction of men using medications with α1-receptor-blocking properties, indicating differential sensitivities to the α-blocking effect among men, and/or additional risk factors that may contribute to the development of priapism. The best predictor for the subsequent development of priapism is a past history of having prolonged and painless erections. The acute management algorithm of APD-induced priapism is the same as for other causes of low-flow priapism. Clinicians should educate patients treated with antipsychotics about the potential for priapism and its sequelae including permanent erectile dysfunction. Appropriate patient education will raise awareness, encourage early reporting, and help reduce the long-term consequences associated with priapism through early intervention. Hwang T, Shah T,Sadeghi-NejadH. A Review of Antipsychotics and Priapism. Sex Med Rev 2021;9:464-471.

Further evidence of anxiety- and depression-like behavior for total genetic ablation of cannabinoid receptor type 1

Cannabinoid receptor type 1 (CB1R) is the most abundant cannabinoid receptor in central nervous system. Clinical studies and animal models have shown that the attenuation of endocannabinoid system signaling correlates with the development of psychiatric disorders such as anxiety, depression and schizophrenia. In the present work, multiple behavioral tests were performed to evaluate behaviors related to anxiety and depression in CB1R+/− and CB1R−/−. CB1R+/− mice had anxiety-related behavior similar to wild type (CB1R+/+) mice, whereas CB1R−/− mice displayed an anxious-like phenotype, which indicates that lower expression of CB1R is sufficient to maintain the neural circuits modulating anxiety. In addition, CB1R−/− mice exhibited alterations in risk assessment and less exploration, locomotion, grooming, body weight and appetite. These phenotypic characteristics observed in CB1R−/− mice could be associated with symptoms observed in human psychiatric disorders such as depression. A better knowledge of the neuromodulatory role of CB1R may contribute to understand scope and limitations of the development of medical treatments.