Affinity For Dopamine Receptors Research Articles

Identification of Novel Quinolone and Quinazoline Alkaloids as Phosphodiesterase 10A Inhibitors for Parkinson's Disease through a Computational Approach.

Phosphodiesterases (PDEs) are vital in signal transduction, specifically by hydrolyzing cAMP and cGMP. Within the PDE family, PDE10A is notable for its prominence in the striatum and its regulatory function over neurotransmitters in medium-spiny neurons. Given the dopamine deficiency in Parkinson's disease (PD) that affects striatal pathways, PDE10A inhibitors could offer therapeutic benefits by modulating D1 and D2 receptor signaling. This study was motivated by the successful history of quinazoline/quinazoline scaffolds in the inhibition of PDE10A. This study involved detailed in silico evaluations through docking followed by pharmacological, pharmacophoric, and pharmacokinetic analyses, prioritizing central nervous system (CNS)-active drug criteria. Seven cyclic peptides, those featuring the quinazoline/quinazoline moiety at both termini, exhibited notably enhanced docking scores compared to those of the remaining alkaloids within the screened library. We identified 7 quinolines and 1 quinazoline including Lepadin G, Aspernigerin, CJ-13536, Aurachin A, 2-Undecyl-4(1H)-quinolone, Huajiaosimuline 3-Prenyl-4-prenyloxyquinolin-2-one, and Isaindigotone that followed the standard CNS active drug criteria. The dominant quinoline ring in our study and its related quinazoline were central to our evaluations; therefore, the pharmacophoric features of these scaffolds were highlighted. The top alkaloids met all CNS-active drug properties; while nonmutagenic and without PAINS alerts, many indicated potential hepatotoxicity. Among the compounds, Huajiaosimuline was particularly significant due to its alignment with lead-likeness and CNS-active criteria. Aspernigerin demonstrated its affinity for numerous dopamine receptors, which signifies its potential to alter dopaminergic neurotransmission that is directly related to PD. Interestingly, the majority of these alkaloids had biological targets primarily associated with G protein-coupled receptors, critical in PD pathophysiology. They exhibit superior excretion parameters and toxicity end-points compared to the standard. Notably, selected alkaloids demonstrated stability in the binding pocket of PDE10A according to the molecular dynamic simulation results. Our findings emphasize the potential of these alkaloids as PDE10A inhibitors. Further experimental studies may be necessary to confirm their actual potency in inhibiting PDE10A before exploring their therapeutic potential in PD.

Anti-craving Property of Chlorpromazine in Pentazocine addiction among sickle cell disease patients: A Case Series

Background: Opioids are useful in the management of vaso-occlusive crisis among Sickle Cell Disease patients; however, there is a need to search for drugs that can ameliorate the withdrawal symptoms without causing further dependence. Case presentations: Three patients living with Sickle cell disease abusing Pentazocine were managed with Tab Chlorpromazine 100mg twice daily for three weeks and had a significant reduction in the level of craving and also experienced improved sleep. Chlorpromazine demonstrates a high affinity for dopamine (DA) receptors and acts as a receptor antagonist by inhibiting adenylate cyclase activity. Conclusion: Chlorpromazine was found to be useful in the management of cravings associated with Pentazocine addiction.

Antipsychotic drug efficacy correlates with the modulation of D1 rather than D2 receptor-expressing striatal projection neurons.

Elevated dopamine transmission in psychosis is assumed to unbalance striatal output through D1- and D2-receptor-expressing spiny-projection neurons (SPNs). Antipsychotic drugs are thought to re-balance this output by blocking D2 receptors (D2Rs). In this study, we found that amphetamine-driven dopamine release unbalanced D1-SPN and D2-SPN Ca2+ activity in mice, but that antipsychotic efficacy was associated with the reversal of abnormal D1-SPN, rather than D2-SPN, dynamics, even for drugs that are D2R selective or lacking any dopamine receptor affinity. By contrast, a clinically ineffective drug normalized D2-SPN dynamics but exacerbated D1-SPN dynamics under hyperdopaminergic conditions. Consistent with antipsychotic effect, selective D1-SPN inhibition attenuated amphetamine-driven changes in locomotion, sensorimotor gating and hallucination-like perception. Notably, antipsychotic efficacy correlated with the selective inhibition of D1-SPNs only under hyperdopaminergic conditions-a dopamine-state-dependence exhibited by D1R partial agonism but not non-antipsychotic D1R antagonists. Our findings provide new insights into antipsychotic drug mechanism and reveal an important role for D1-SPN modulation.

Discovery of Selective Dopamine Receptor Ligands Derived from (-)-Stepholidine via C-3 Alkoxylation and C-3/C-9 Dialkoxylation.

We evaluated C-3 alkoxylated and C-3/C-9 dialkoxylated (-)-stepholidine analogues to probe the tolerance at the C-3 and C-9 positions of the tetrahydroprotoberberine (THPB) template toward affinity for dopamine receptors. A C-9 ethoxyl substituent appears optimal for D1R affinity since high D1R affinities were observed for compounds that contain an ethyl group at C-9, with larger C-9 substituents tending to decrease D1R affinity. A number of novel ligands were identified, such as compounds 12a and 12b, with nanomolar affinities for D1R and no affinity for either D2R or D3R, with compound 12a being identified as a D1R antagonist for both G-protein- and β-arrestin-based signaling. Compound 23b was identified as the most potent and selective D3R ligand containing a THPB template to date and functions as an antagonist for both G-protein- and β-arrestin-based signaling. Molecular docking and molecular dynamics studies validated the D1R and D3R affinity and selectivity of 12a, 12b, and 23b.

Design, Synthesis, Molecular Docking, and Biological Evaluation of Novel Pimavanserin-Based Analogues as Potential Serotonin 5-HT2A Receptor Inverse Agonists.

There is concern for important adverse effects with use of second-generation antipsychotics in Parkinson's disease psychosis (PDP) and dementia-related psychosis. Pimavanserin is the only antipsychotic drug authorized for PDP and represents an inverse agonist of 5-HT2A receptors (5-HT2AR) lacking affinity for dopamine receptors. Therefore, the development of serotonin 5-HT2AR inverse agonists without dopaminergic activity represents a challenge for different neuropsychiatric disorders. Using ligand-based drug design, we discovered a novel structure of pimavanserin analogues (2, 3, and 4). In vitro competition receptor binding and functional G protein coupling assays demonstrated that compounds 2, 3, and 4 showed higher potency than pimavanserin as 5-HT2AR inverse agonists in the human brain cortex and recombinant cells. To assess the effect of molecular substituents for selectivity and inverse agonism at 5-HT2ARs, molecular docking and in silico predicted physicochemical parameters were performed. Docking studies were in agreement with in vitro screenings and the results resembled pimavanserin.

Pharmacokinetic and Pharmacologic Characterization of the Dihydrotetrabenazine Isomers of Deutetrabenazine and Valbenazine.

Valbenazine and deutetrabenazine are vesicular monoamine transporter 2 (VMAT2) inhibitors approved for tardive dyskinesia. The clinical activity of valbenazine is primarily attributed to its only dihydrotetrabenazine (HTBZ) metabolite, [+]-α-HTBZ. Deutetrabenazine is a deuterated form of tetrabenazine and is metabolized to four deuterated HTBZ metabolites: [+]-α-deuHTBZ, [+]-β-deuHTBZ, [-]-α-deuHTBZ, and [-]-β-deuHTBZ. An open-label, crossover study characterized the pharmacokinetic profiles of the individual deuHBTZ metabolites, which have not been previously reported. VMAT2 inhibition and off-target interactions of the deuHTBZ metabolites were evaluated using radioligand binding. The only valbenazine HTBZ metabolite, [+]-α-HTBZ, was a potent VMAT2 inhibitor, with negligible affinity for off-target dopamine, serotonin, and adrenergic receptors. Following deutetrabenazine administration, [-]-α-deuHTBZ represented 66% of circulating deuHTBZ metabolites and was a relatively weak VMAT2 inhibitor with appreciable affinity for dopamine (D2S , D3 ) and serotonin (5-HT1A , 5-HT2B , 5-HT7 ) receptors. [+]-β-deuHTBZ was the most abundant deuHTBZ metabolite that potently inhibited VMAT2, but it represented only 29% of total circulating deuHTBZ metabolites. The mean half-life of [+]-α-HTBZ (22.2hours) was ∼3× longer than that of [+]-β-deuHTBZ (7.7hours). These findings are similar to studies with tetrabenazine, in that deutetrabenazine is metabolized to four deuHTBZ stereoisomers, the most abundant of which has negligible interaction with VMAT2 in vitro and appreciable affinity for several off-target receptors. In contrast, valbenazine's single HTBZ metabolite is a potent VMAT2 inhibitor in vitro with no discernible off-target activity. Determination of the effects of intrinsic/extrinsic variables on deutetrabenazine's safety/efficacy profile should incorporate assessment of the effects on all deuHTBZ metabolites.

It’s Dopamine and Schizophrenia All Over Again

Dopamine (DA) has been hovering over schizophrenia for 70 years, with the earliest clues of a connection between the two coming from clinical reports that psychotic symptoms tended to diminish in chronically institutionalized individuals with schizophrenia who developed Parkinson’s disease. It became the “dopamine hypothesis” based on 3 seminal observations: 1) that dopamimetic drugs like amphetamine can induce paranoid states; 2) that, as shown by Nobel Laureate Arvid Carlsson, antipsychotic drugs influence DA metabolism; and 3) that, as shown by Lasker Awardee Sol Snyder, the clinical potency of antipsychotic drugs is remarkably correlated with their in vitro affinity for DA receptors.

P599. The Muscarinic Agonist Xanomeline Demonstrates Standalone Activity and Augments Clinical Antipsychotics in Rodent Behavioral Models of Psychosis

Evidence indicates that muscarinic acetylcholine receptor agonists exhibit antipsychotic properties. Xanomeline, a centrally active M1 and M4 receptor agonist, is devoid of any direct dopamine receptor affinity or activity. An important question is whether xanomeline can also augment the effects of existing antipsychotics. Two rodent behavioral models were used to test combinations of xanomeline and either risperidone or aripiprazole. The conditioned avoidance response (CAR) and psychostimulant-induced locomotor activity (LMA) assays are commonly used behavioral tests in rodents that have good predictive validity for detecting antipsychotic activity.

FATIGUE IN MULTIPLE SCLEROSIS

The article discusses and analyzes literature data on the phenomenon of fatigue in patients with multiple sclerosis. More than 80% patients with multiple sclerosis complain of fatigue, which significantly limits their functional capacity and negatively affects the quality of life. In general, fatigue is a complex, multidimensional phenomenon that consists of subjective (one's own feeling of fatigue) and objective (quantitative characteristics of fatigue when performing a certain activity) components. At present, the most accessible method of fatigue assessment is patient survey. In multiple sclerosis, fatigue can be primary (as a direct consequence of the disease) or secondary (as a consequence of reduced functional capabilities, sleep disorders, chronic pain, side effects of medications, etc). In general, fatigue in multiple sclerosis is a heterogeneous phenomenon based on various etiopathogenetic mechanisms. We reviewed neuroimaging markers of global and focal lesions of the white and gray matter of the brain that are associated with the presence of fatigue in patients with multiple sclerosis. The impact of peripheral immune-inflammatory processes on the fatigue occurrence was shown which was realized via humoral, cellular, and neuronal mechanisms. We analyzed the role of inflammatory processes in the brain and spinal cord in the form of activation of microglia with hyperproduction of cytokines, which ultimately disrupts dopamine metabolism and reduces the affinity of dopamine receptors. The excess activity of certain functional components of the nervous system in the form of higher engagement of the motor structures of the brain and spinal cord during the performance of standard motor tasks was highlighted. The role of disruption of interoceptive mechanisms (perception and monitoring of the body's internal environment via hormonal, immune, metabolic, temperature, pain, and visceromotor signals) in the occurrence of fatigue in multiple sclerosis was shown. The paper underlines modern principles of fatigue correction based on these mechanisms.

N-Skatyltryptamines-Dual 5-HT6R/D2R Ligands with Antipsychotic and Procognitive Potential.

A series of N-skatyltryptamines was synthesized and their affinities for serotonin and dopamine receptors were determined. Compounds exhibited activity toward 5-HT1A, 5-HT2A, 5-HT6, and D2 receptors. Substitution patterns resulting in affinity/activity switches were identified and studied using homology modeling. Chosen hits were screened to determine their metabolism, permeability, hepatotoxicity, and CYP inhibition. Several D2 receptor antagonists with additional 5-HT6R antagonist and agonist properties were identified. The former combination resembled known antipsychotic agents, while the latter was particularly interesting due to the fact that it has not been studied before. Selective 5-HT6R antagonists have been shown previously to produce procognitive and promnesic effects in several rodent models. Administration of 5-HT6R agonists was more ambiguous—in naive animals, it did not alter memory or produce slight amnesic effects, while in rodent models of memory impairment, they ameliorated the condition just like antagonists. Using the identified hit compounds 15 and 18, we tried to sort out the difference between ligands exhibiting the D2R antagonist function combined with 5-HT6R agonism, and mixed D2/5-HT6R antagonists in murine models of psychosis.

TPN672: A Novel Serotonin-Dopamine Receptor Modulator for the Treatment of Schizophrenia.

TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine receptors that is currently in clinical trial for the treatment of psychiatric disorders. In vitro binding study showed that TPN672 exhibited extremely high affinity for serotonin 1A receptor (5-HT1AR) (K i = 0.23 nM) and 5-HT2AR (K i = 2.58 nM) as well as moderate affinity for D3R (K i = 11.55 nM) and D2R (K i = 17.91 nM). In vitro functional assays demonstrated that TPN672 acted as a potent 5-HT1AR agonist, D2R/D3R partial agonist, and 5-HT2AR antagonist. TPN672 displayed robust antipsychotic efficacy in rodent models (e.g., blocking phencyclidine-induced hyperactivity), significantly better than aripiprazole, and ameliorated negative symptoms and cognitive deficits in the sociability test, dark avoidance response, Morris water maze test, and novel object recognition test. The results of electrophysiological experiments showed that TPN672 might inhibit the excitability of the glutamate system through activating 5-HT1AR in medial prefrontal cortex, thereby improving cognitive and negative symptoms. Moreover, the safety margin (the ratio of minimum catalepsy-inducing dose to minimum effective dose) of TPN672 was about 10-fold, which was superior to aripiprazole. In conclusion, TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having lower risk of extrapyramidal symptoms and hyperprolactinemia. SIGNIFICANCE STATEMENT: TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having a lower risk of extrapyramidal symptoms and hyperprolactinemia. A phase I clinical trial is now under way to test its tolerance, pharmacokinetics, and pharmacodynamic effects in human volunteers. Accordingly, the present results will have significant impact on the development of new antischizophrenia drugs.

Discovery of a new class of multi-target heterocycle piperidine derivatives as potential antipsychotics with pro-cognitive effect

A series of benzoisoxazoleylpiperidine derivatives were synthesized by using the multi-target strategies and their potent affinities for dopamine (DA), serotonin (5-HT) and human histamine H3 receptors have been evaluated. Of these compounds, the promising candidate 4w displayed high affinities for D2, D3, 5-HT1A, 5-HT2A and H3, a moderate affinity for 5-HT6, negligible effects on the human ether-a-go-go-related gene (hERG) channel, low affinities for off-target receptors (5-HT2C, adrenergic α1 and H1). In addition, the animal behavioral study revealed that, compared to risperidone, compound 4w significantly inhibited apomorphine-induced climbing and MK-801-induced movement behaviors with a high threshold for catalepsy and low liabilities for weight gain and hyperprolactinemia. Results from the conditioned avoidance response test and novel object recognition task demonstrated that 4w had pro-cognitive effects. Thus, the antipsychotic drug-like activities of 4w indicate that it may be a potential polypharmacological antipsychotic candidate drug.

Substituted phenothiazines: synthesis and in silico evaluation of D4 dopamine receptor inhibition

In the present paper we describe synthesis and molecular docking simulation of substituted phenothiazines. Halonitrobenzenes on reaction with thiols give 2-amino-2′-nitrodiphenylsulphides which on formylation with 90% formic acid yield 2-formamido-2′-nitrodiphenyl sulfides. This compound undergoes Smiles rearrangement to provide phenothiazines. To evaluate the antipsychotic property of the synthesized phenothiazines derivatives (5a–d and 7), molecular docking simulation study were performed into the binding pocket of D4 dopamine receptor. These compounds have shown acceptable binding affinity with the binding pocket of the D4 dopamine receptor similar to known inhibitors. Whereas, compound 7 has displayed higher affinity for D4 dopamine receptor compared to D3 and D2 receptors. All compounds interacted with critical residues for the inhibition of D4 dopamine receptor and hence can be developed as potent antipsychotic drugs.

Synthesis, pharmacological evaluations, and molecular docking studies on a new 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework: Rigidification of D1 receptor selective 1-phenylbenzazepines and discovery of a new 5-HT6 receptor scaffold.

The novel 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework, a structurally rigidified variant of the 1-phenylbenzazepine template, was synthesized via direct arylation as a key reaction. Evaluation of the binding affinities of the rigidified compounds across a battery of serotonin, dopamine, and adrenergic receptors indicates that this scaffold unexpectedly has minimal affinity for D1 and other dopamine receptors and is selective for the 5-HT6 receptor. The affinity of these systems at the 5-HT6 receptor is significantly influenced by electronic and hydrophobic interactions as well as the enhanced rigidity of the ligands. Molecular docking studies indicate that the reduced D1 receptor affinity of the rigidified compounds may be due in part to weaker H-bonding interactions between the oxygenated moieties on the compounds and specific receptor residues. Key receptor-ligand H-bonding interactions, salt bridges, and π-π interactions appear to be responsible for the 5-HT6 receptor affinity of the compounds. Compounds 10 (6,7-dimethoxy-2,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine) and 12 (6,7-dimethoxy-2-methyl-2,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine) have been identified as structurally novel, high affinity (Ki =5nM), selective 5-HT6 receptor ligands.

L-Tetrahydropalmatine, a Novel Dopamine Antagonist, Fails to Improve Psychiatric Symptoms as Adjunctive Treatment for Schizophrenia

Abstract Schizophrenia is a complex mental illness characterized by positive and negative symptoms. Antipsychotic medications are the main treatment for this condition; however, many patients have only a partial response. All currently available antipsychotics involve modulation of the dopamine system, although the underlying pathophysiology of this illness remains poorly understood. Increasing evidence suggests that inflammation plays a significant role in the development of schizophrenia. Thus, a medication that modulates both dopamine signaling and inflammation may be a promising treatment for schizophrenia. L-tetrahydropalmatine (l-THP) has modest affinity for dopamine receptors, acting as an antagonist at D1, D2, and D3 receptors. L-THP also has anti-inflammatory effects, decreasing levels of tumor necrosis factor-α and interleukin 6. We performed a 4-week, randomized, double-blind, placebo-controlled trial of oral l-THP (30 mg twice daily) as an adjunctive treatment in 63 adults with schizophrenia (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) on stable antipsychotic medication. The primary psychiatric outcome measures were the presence of positive and negative symptoms. Plasma concentrations of 11 cytokines and C-reactive protein (CRP) were also measured. L-THP had no significant effect on any psychiatric measure but was well tolerated and associated with a significant decrease in extrapyramidal symptoms. L-THP significantly increased plasma concentrations, compared with placebo, of two inflammatory markers: soluble intracellular adhesion molecule 1 and CRP. These findings do not support the efficacy of L-THP as an add-on treatment for schizophrenia but suggest that L-THP may have previously unrecognized proinflammatory effects in people with this disease.

Síndrome neuroléptico maligno inducido por risperidona y facilitado por sepsis de origen urinario: clínica y fisiopatología.

La risperidona es un antagonista selectivo monoaminérgico, con una elevada afinidad por receptores dopaminérgicos, que puede producir síndrome neuroléptico maligno (SNM), considerado una emergencia médica con alto riesgo de muerte. Tiene una incidencia de hasta el 3% y su mortalidad está entre el 10 y 20%. Se reporta el caso de una paciente de 56 años, que reunía los criterios clínicos del SNM, inducido por el uso de risperidona y facilitado por una sepsis de origen urinario. El tratamiento se condujo con un agente agonista dopaminérgico y cambio del antipsicótico, procedimientos que resultaron en una adecuada evolución clínica. El SNM es una entidad de baja prevalencia, para la cual existen criterios diagnósticos con especificidad y sensibilidad mayor del 90%, por lo que debe diferenciarse claramente de otras patologías. Se discute el mecanismo mediante el cual la infección urinaria facilitaría la ocurrencia de esta enfermedad. El diagnóstico precoz mejora la respuesta al manejo adecuado que se establezca en cada caso.

Effect of Metformin on Antipsychotic-Induced Metabolic Dysfunction: The Potential Role of Gut-Brain Axis.

Antipsychotics are the first-line medications prescribed for patients with schizophrenia or other mental disorders. Cumulative evidence has revealed that metabolic dysfunctions frequently occur in patients receiving antipsychotics, especially second-generation antipsychotics, and these effects may decrease patient compliance and increase health costs. Metformin is an effective pharmaceutical adjuvant for ameliorating antipsychotic-induced metabolic dysfunction (AIMD) in clinical practice. However, the mechanism of the effects of metformin on AIMD remains unclear. The gut-brain axis is a bidirectional communication system between the gastrointestinal tract and the central nervous system and has been associated with many pathological and physiological conditions, such as those related to metabolism. Antipsychotics interact with and have affinity for dopamine receptors and other receptors in the brain, and treatment with these antipsychotics has been shown to influence gut microbiota metabolism and composition, as observed in both animal and human studies. Metformin exerts an antidiabetic effect that is correlated with activation of AMP-kinase in the hypothalamus, and metformin also influences gut flora. Therefore, the gut-brain axis may play a role in the effect of metformin on AIMD. Since no direct evidence is available, this perspective may provide a direction for further research.

24.1 VERBAL COMMUNICATION DISORDERS IN SCHIZOPHRENIA SPECTRUM PATIENTS: SYMPTOM AND SIDE EFFECT

Background: Verbal communication disturbances are a key diagnostic feature of schizophrenia. These disturbances present in different aspects, which can be assessed by looking at form and meaning. However, research on this topic is often confounded by the effects of antipsychotic medication. It therefore remains unclear which aspects of language production are influenced by antipsychotics, and which disturbances can be viewed as true psychotic symptoms. Automated language analysis has recently shown to be a useful tool to characterize verbal communication disturbances in schizophrenia. Methods: The spoken language of 42 healthy controls and 48 patients with a schizophrenia spectrum disorder was recorded using a semi-structured interview designed to elicit spontaneous speech in a natural setting. The audio was analyzed for measures of speed and quantity. For a subset of participants, the transcribed interview was analyzed using a novel Natural Language Processing (NLP) word2vec model to quantify incoherence. For patients, dopamine receptor affinity of their antipsychotic drug was estimated. Symptom severity was assessed by means of the Positive and Negative Syndrome Scale (PANSS). Results: Overall, schizophrenia spectrum patients spoke slower and produced fewer words than the healthy controls. Language measures revealed medium to strong correlations with PANSS negative and general scores. Usage of antipsychotics with strong D2 receptor affinity was found to have the strongest effect on speech. Word2vec trained models were able to differentiate between patients and controls. Conclusions: Automated assessments of aspects of verbal communication show promise in elucidating and quantifying various symptoms. Our results indicate that usage of antipsychotic medication has a marked effect on verbal communication in addition to disturbances that are better interpreted as part of the illness. These medication-effects should be taken into account when analyzing language disturbances in schizophrenia. Word2vec proved to be a useful tool to differentiate between subjects and controls, reflecting disturbances in both meaning and structure in verbal communication. This research illustrates the possibilities in automated assessment of language which can serve as measures of symptom severity, medication effects and open the door to diagnosis and prognosis.

Antipsychotics for patients with pain.

Going back to basics prior to mentioning the use of antipsychotics in patients with pain, the International Association for the Study of Pain (IASP) definition of pain can be summarized as an unpleasant experience, composed of sensory experience caused by actual tissue damage and/or emotional experience caused by potential tissue damage. Less used than antidepressants, antipsychotics have also been used for treating this unpleasant experience as adjuvant analgesics without sufficient evidence from research. Because recently developed atypical antipsychotics reduce the adverse reactions of extrapyramidal symptoms, such as acute dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia caused by typical antipsychotics, they are expected to be used more frequently in various painful conditions, while increasing the risk of metabolic syndromes (weight gain, diabetes, and dyslipidemia). Various antipsychotics have different neurotransmitter receptor affinities for dopamine (D), 5-hydroxytryptamine (5-HT), adrenergic (α), histamine (H), and muscarinic (M) receptors. Atypical antipsychotics antagonize transient, weak D2 receptor bindings with strong binding to the 5-HT2A receptor, while typical antipsychotics block long-lasting, tight D2 receptor binding. On the contrary, antidepressants in the field of pain management also block the reuptake of similar receptors, mainly on the 5-HT and, next, on the norepinephrine, but rarely on the D receptors. Antipsychotics have been used for treating positive symptoms, such as delusion, hallucination, disorganized thought and behavior, perception disturbance, and inappropriate emotion, rather than the negative, cognitive, and affective symptoms of psychosis. Therefore, an antipsychotic may be prescribed in pain patients with positive symptoms of psychosis during or after controlling all sensory components.

Pharmacological characterization of the LSD analog N-ethyl-N-cyclopropyl lysergamide (ECPLA).

The lysergamide lysergic acid diethylamide (LSD) is a prototypical classical hallucinogen with remarkably high potency. LSD remains a popular recreational drug but is also becoming an important research tool for medical and neuroscience studies. Recently, several lysergamides that are close structural analogs of LSD have been sold as recreational drugs, which suggests that further studies are needed to explore the pharmacological properties of these compounds. In this present investigation, another LSD congener, N-ethyl-N-cyclopropyl lysergamide (ECPLA), which to date has not been marketed as a recreational substance, was evaluated for its pharmacological features relative to those previously reported for LSD. The experiments focused on interactions with the 5-HT2A receptor, which is responsible for mediating the psychedelic effects of LSD and other hallucinogens. Competitive binding assays were performed to measure the affinity of ECPLA for 27 monoamine receptors. The ability of ECPLA to activate human 5-HT2 receptor subtypes was assessed using calcium mobilization assays. Head twitch response (HTR) studies were conducted in C57BL/6J mice to determine whether ECPLA activates 5-HT2A receptors in vivo. Two other N-alkyl substituted lysergamides, N-methyl-N-isopropyl lysergamide (MIPLA) and N-methyl-N-propyl lysergamide (LAMPA), were also tested in the HTR paradigm for comparative purposes. ECPLA has high affinity for most serotonin receptors, α2-adrenoceptors, and D2-like dopamine receptors. Additionally, ECPLA was found to be a potent, highly efficacious 5-HT2A agonist for Gq-mediated calcium flux. Treatment with ECPLA induced head twitches in mice with a median effective dose (ED50) of 317.2nmol/kg (IP), which is ~ 40% of the potency observed previously for LSD. LAMPA (ED50 = 358.3nmol/kg) was virtually equipotent with ECPLA in the HTR paradigm whereas MIPLA (ED50 = 421.7nmol/kg) was slightly less potent than ECPLA. These findings demonstrate that the pharmacological properties of ECPLA, MIPLA, and LAMPA are reminiscent of LSD and other lysergamide hallucinogens.