Monoamine Receptors Research Articles

Drugs with glutamate-based mechanisms of action in psychiatry.

Psychopharmacotherapy of major psychiatric disorders is mostly based on drugs that modulate serotonergic, dopaminergic, or noradrenergic neurotransmission, either by inhibiting their reuptake or by acting as agonists or antagonists on specific monoamine receptors. The effectiveness of this approach is limited by a significant delay in the therapeutic mechanism and self-perpetuating growth of treatment resistance with a consecutive number of ineffective trials. A growing number of studies suggest that drugs targeting glutamate receptors offer an opportunity for rapid therapeutic effect that may overcome the limitations of monoaminergic drugs. In this article, we present a review of glutamate-modulating drugs, their mechanism of action, as well as preclinical and clinical studies of their efficacy in treating mental disorders. Observations of the rapid, robust, and long-lasting effects of ketamine and ketamine encourages further research on drugs targeting glutamatergic transmission. A growing number of studies support the use of memantine and minocycline in major depressive disorder and schizophrenia. Amantadine, zinc, and Crocus sativus extracts yield the potential to ameliorate depressive symptoms in patients with affective disorders. Drugs with mechanisms of action based on glutamate constitute a promising pharmacological group in the treatment of mental disorders that do not respond to standard methods of therapy. However, further research is needed on their efficacy, safety, dosage, interactions, and side effects, to determine their optimal clinical use.

CCNP Innovations in Neuropsychopharmacology Award: The psychopharmacology of psychedelics: where the brain meets spirituality.

For 3000 years, psychedelics have been used in religious contexts to enhance spiritual thinking, well-being, and a sense of community. In the last few years, a renaissance in the use of psychedelic drugs for mental disorders has occurred in Western society; consequently, a pressing scientific need to elucidate the intricate mechanisms underlying their actions has arisen. Psychedelics mainly bind to serotonin (5-HT) receptors, particularly 5-HT2A receptors, but may also bind to other receptors. Unlike conventional psychotropic drugs used in psychiatry, psychedelics introduce a distinctive complexity. They not only engage in receptor activation, but also exert influence over specific neural circuits, thereby facilitating transformative cognitive experiences and fostering what many have identified as a spiritual contemplation or mystical experience. This comprehensive review describes clinical studies that have examined the propensity of psychedelics to enhance spiritual, mystical, and transcendent cognitive states. This multifaceted nature, encompassing diverse components and paradigms, necessitates careful consideration during the investigation of psychedelic mechanisms of action to avoid oversimplification. The present review endeavours to elucidate the mechanisms underlying the actions of 2 principal psychedelic substances, psilocybin and lysergic acid diethylamide (LSD), with a focus on monoamine and glutamate receptor mechanisms; molecular aspects, such as neuroplasticity and epigenetics; as well as the impact of psychedelics on brain circuits, including the default mode network and the cortico-striato-thalamo-cortical network. Given their distinctive and intricate mechanisms of action, psychedelics necessitate a novel conceptual framework in psychiatry, offering insight into the treatment of mental health disorders and facilitating the integration of the realms of brain, mind, and spirituality.

Biological sex modulates the efficacy of 2,5-dimethoxy-4-iodoamphetamine (DOI) to mitigate fentanyl demand

BackgroundOverdose deaths remain high for opioid use disorder, emphasizing the need to pursue innovative therapeutics. Classic psychedelic drugs that engage many monoamine receptors mitigate opioid use. Here, we tested the hypothesis that the preferential serotonin 5-HT2AR agonist, 2,5-dimethoxy-4-iodoamphetamine (DOI) could reduce the demand for fentanyl in a preclinical model of fentanyl self-administration. MethodsMale and female Sprague-Dawley rats (n = 25–29) were implanted with indwelling jugular catheters and allowed to self-administer fentanyl (3.2μg/kg/infusion). Rats progressed to a novel low price twice within-session threshold procedure where rats sampled the lowest price twice before decreasing the dose of fentanyl by a ¼ log every 10minutes across 11 doses. Once stable, rats were pretreated with saline or DOI (0.01, 0.03, 1mg/kg). Fentanyl consumption was analyzed using an exponentiated demand function to extract the dependent variables, Q0 and α. ResultsMale and female rats acquired fentanyl self-administration in the lowest price twice within-session threshold procedure. DOI dose-dependently altered fentanyl intake such that 5-HT2AR activation decreased Q0 in female rats but increased Q0 in male rats. For demand elasticity, DOI increased α in male rats but did not alter α in female rats. DOI did not alter inactive lever presses or latency. ConclusionDOI reduces consumption at minimally constrained costs but did not affect the reinforcement value of fentanyl in female rats. Alternatively, DOI significantly reduced the reinforcement value of fentanyl in male rats. Biological sex alters the therapeutic efficacy of DOI and 5-HT2AR activation sex-dependently alters opioid reinforcement.

Synthetic Cathinones: Epidemiology, Toxicity, Potential for Abuse, and Current Public Health Perspective.

Synthetic cathinones, derived from cathinone found in the plant Catha edulis, represent the second largest and most frequently seized group of new psychoactive substances. They are considered as β-keto analogs of amphetamine, sharing pharmacological effects with amphetamine and cocaine. This review describes the neurotoxic properties of synthetic cathinones, encompassing their capacity to induce neuroinflammation, dysregulate neurotransmitter systems, and alter monoamine transporters and receptors. Additionally, it discusses the rewarding and abuse potential of synthetic cathinones drawing from findings obtained through various preclinical animal models, contextualized with other classical psychostimulants. The review also offers an overview of current abuse trends of synthetic cathinones on the illicit drug market, specifying the aspects covered, and underscores the risks they pose to public health. Finally, the review discusses public health initiatives and efforts to reduce the hazards of synthetic cathinones, including harm reduction methods, education, and current clinical management strategies.

Enantiomeric contributions to methamphetamine's bidirectional effects on basal and fentanyl-depressed respiration in mice

RationaleFentanyl remains the primary cause of fatal overdoses, and its co-use with methamphetamine (METH) is a growing concern. We previously demonstrated that racemic METH can either enhance or mitigate opioid-induced respiratory depression (OIRD) dependent upon whether a low or high dose is administered. The optical isomers of METH, dextromethamphetamine (d-METH) and levomethamphetamine (l-METH), differ substantially in their selectivity and potency to activate various monoamine (MA) receptors, and these pharmacological differences may underlie the bidirectional effects of the racemate. Since it is unknown which of METH's MA receptor mechanisms mediate these respiratory effects, examination of METH's pharmacologically distinct enantiomers may provide insight into treatment targets for OIRD. MethodsThe two optical isomers of METH, d-METH and l-METH, were tested in adult male mice to determine their effects on basal and fentanyl-depressed respiratory frequency, tidal volume, and minute ventilation (MVb; i.e., respiratory frequency x tidal volume) using whole-body plethysmography. ResultsWhen tested at dose ranges of 1.0–10 mg/kg, d-METH elevated MVb and l-METH decreased basal MVb. A dose of 30 mg/kg l-METH increased basal MVb. Under fentanyl-depressed conditions, the bidirectional effects of racemic METH were observed with d-METH treatment while l-METH significantly exacerbated OIRD at 1.0 and 3.0 mg/kg. Conclusionsd-METH and l-METH differentially contribute to the bidirectional respiratory modulation observed by the racemate, with d-METH exhibiting predominantly stimulatory effects and l-METH exhibiting primarily depressant effects depending on dose.

Recognition of methamphetamine and other amines by trace amine receptor TAAR1.

Trace amine-associated receptor 1 (TAAR1), the founding member of a nine-member family of trace amine receptors, is responsible for recognizing a range of biogenic amines in the brain, including the endogenous β-phenylethylamine (β-PEA)1 as well as methamphetamine2, an abused substance that has posed a severe threat to human health and society3. Given its unique physiological role in the brain, TAAR1 is also an emerging target for a range of neurological disorders including schizophrenia, depression and drug addiction2,4,5. Here we report structures of human TAAR1-G-protein complexes bound to methamphetamine and β-PEA as well as complexes bound to RO5256390, a TAAR1-selective agonist, and SEP-363856, a clinical-stage dual agonist for TAAR1 and serotonin receptor 5-HT1AR (refs. 6,7). Together with systematic mutagenesis and functional studies, the structures reveal the molecular basis of methamphetamine recognition and underlying mechanisms of ligand selectivity and polypharmacology between TAAR1 and other monoamine receptors. We identify a lid-like extracellular loop 2 helix/loop structure and a hydrogen-bonding network in the ligand-binding pockets, which may contribute to the ligand recognition in TAAR1. These findings shed light on the ligand recognition mode and activation mechanism for TAAR1 and should guide the development of next-generation therapeutics for drug addiction and various neurological disorders.

Wistar Kyoto rats exhibit decreased serotonin neuronal firing and increased norepinephrine burst activity but dampened hippocampal α2-adrenoceptor sensitivity.

Wistar Kyoto (WKY) rats manifest abnormalities in the function of monoamine receptors and transporters, as well as levels of these neurotransmitters in the brain. The present study assessed alterations in the firing activity of serotonin (5-hydroxytryptamine [5-HT]), norepinephrine (NE), and dopamine (DA) neurons, as well as the activity of 5-HT and NE receptors and transporters in the hippocampus. In vivo electrophysiological recordings were conducted in male WKY and Wistar rats. Extracellular single-unit recordings of 5-HT, NE, and DA neurons were performed. Recordings of pyramidal neurons were conducted in the medial prefrontal cortex (mPFC) and the hippocampus, where direct application of 5-HT and NE by iontophoresis was also carried out. The mean firing rate of 5-HT neurons was significantly decreased in WKY compared to Wistar rats. The burst activity of NE neurons was significantly increased in WKY, while their mean firing activity was not changed. There was no alteration in the firing, burst, and population activity of DA neurons in WKY animals. In the hippocampus, a decrease in sensitivity of α2-adrenoceptors, but not 5-HT receptors, was observed. There was, however, no change in the activity of 5-HT and NE transporters. The firing activity of mPFC pyramidal neurons was similar in WKY versus Wistar rats. In WKY rats, there was a decrease in the firing activity of 5-HT neurons. There was also an enhanced burst activity of NE neurons, accompanied by a reduction in sensitivity of the α2-adrenoceptor in the hippocampus, inferring a decrease in NE transmission.

Broiler Heart Muscle Monoaminergic Receptors Alteration in Response to Chronic Heat Stress: Based on Transcription Analysis.

Chronic heat stress affects numerous physiological and behavioral mechanisms. Epigenetic changes following prolonged cyclic heat stress, creating new opportunities for molecular biology research. One of these changes involves monoamines, such as serotonin, epinephrine, norepinephrine, dopamine, and their transmission. Broiler chickens are highly susceptible to heat stress, and their hearts become insufficient during the growth phase, leading to hypertrophy of the left heart. RNA-seq data were obtained from NCBI with accession number SRP082125. The expression level of genes was determined with DESeq2 packages. Gene Ontology qualification, including biological processes, cellular components, and molecular role (MF), was performed from the Gene Ontology Resource. Cyclic heat stress in broilers significantly altered monoamine receptor expression. Twenty-nine genes of the monoamine pathway changed their expression in the left heart. Significant downregulation of expression was statistically associated with the ADRB1, HTR2A, and PNMT genes and upregulation of the MAOA gene (P<0.01). STRING database was used to construct the protein-protein interaction network; based on network analysis, the HTR2C, HTR2A, and HTR5A genes were identified as the major nodal genes in the network followed by MAOA, DRD2, DRD5, HTR1B, DRD1, DRD3, and HTR2B genes occupying the second important place in the network module. In conclusion, heat stress treatment prevented cardiac hypertrophy and altered the expression of monoamine genes. This would imply that monoamine transmission plays an important role in the development of cardiac hypertrophy, and that cyclic-chronic heat treatment modulates the cardiac monoaminergic system. These molecular biomarkers could be useful for screening, diagnosis, and treatment of cardiac hypertrophy.

The Expression of Trace Amine-Associated Receptors (TAARs) in Breast Cancer Is Coincident with the Expression of Neuroactive Ligand-Receptor Systems and Depends on Tumor Intrinsic Subtype.

Currently, the contribution of trace amine-associated receptors (TAARs) to breast cancer (BC) is recognized, but their associations with various pathological characteristics are not yet understood. There is accumulated transcriptomic data for BC tumors, which are represented in publicly accessible databases. We estimated TAARs' (including TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, and TAAR9) associations with BC stage, grade, and molecular subtypes in these data and identified that the expression of all TAARs was associated with more unfavorable cancer subtypes, including basal-like and HER2-positive tumors. Also, the significant upregulation of all TAARs was demonstrated in circulating tumor cells compared to the metastatic lesions. Considering that co-expressed genes are more likely to be involved in the same biologic processes, we analyzed genes that are co-expressed with TAARs in BC. These gene sets were enriched with the genes of the olfactory transduction pathway and neuroactive ligand-receptor interaction participants. TAARs are co-expressed with G-protein-coupled receptors of monoamine neurotransmitters including dopamine, norepinephrine, and serotonin as well as with other neuroactive ligand-specific receptors. Since TAAR1 is able to modulate the activity of monoamine receptors that are involved in the regulation of BC growth, TAAR1 and potentially other TAARs may be regarded as prospective therapeutic targets for breast cancer.

Chronic unpredictable stress induces depression/anxiety-related behaviors and alterations of hippocampal monoamine receptor mRNA expression in female mice at different ages

Depression and anxiety are the most common mental health disorders. Though they affect people at any age and occur more often in females, the pathophysiological changes under these conditions are less investigated. In the present study, we examined the effects of age and stress on depression- and anxiety-related behaviors in female mice. Saccharin preference and the open field test were carried out before and after chronic unpredictable stress in 4-, 14- and 25-month-old female mice. After behavioral tests, mRNA levels of monoamine receptors in the hippocampus were measured by real-time RT-PCR. Chronic unpredictable stress decreased saccharin preference in 4-, 14- and 25-month-old mice and the time spent in the center in the open field test in 25-month-old mice. For monoamine receptors, analysis of variance revealed significant effects of age on mRNA levels of Htr1a, Htr2a, Htr6, Adra1a, Adrb2, and Adrb3, significant effects of stress on mRNA levels of Htr4, Adra2c, Adrb1, and Adrb2, and interactions of age × stress on mRNA levels of Htr1a, Htr5b, Adra1d, Adra2a, Adra2c, and Adrb1. Chronic unpredictable stress decreased mRNA levels of Htr4, Htr5b, Adra2c, and Adrb1 in 4-month-old female mice. Correlations were observed between saccharin preference and mRNA levels of Htr4, Htr5b, Htr6, Adra1d, Adra2a, and Adra2c in 4-month-old mice and between the time spent in the center in the open field test and mRNA levels of Htr1b in 4-month-old mice, Htr3a, Htr7, and Adrb2 in 14-month-old mice, and Drd2 in 4- and 14-month-old mice. Our findings support that stress induces depression- and anxiety-related behaviors and the expression of hippocampal monoamine receptors in an age-dependent manner in female mice.

Enhanced L-β-Aminoisobutyric Acid Is Involved in the Pathophysiology of Effectiveness for Treatment-Resistant Schizophrenia and Adverse Reactions of Clozapine.

Clozapine is an effective antipsychotic for the treatment of antipsychotic-resistant schizophrenia; however, specific types of A/B adverse effects and clozapine-discontinuation syndromes are also well known. To date, both the critical mechanisms of clinical actions (effective for antipsychotic-resistant schizophrenia) and the adverse effects of clozapine remain to be elucidated. Recently, we demonstrated that clozapine increased the synthesis of L-β-aminoisobutyric acid (L-BAIBA) in the hypothalamus. L-BAIBA is an activator of the adenosine monophosphate-activated protein kinase (AMPK), glycine receptor, GABAA receptor, and GABAB receptor (GABAB-R). These targets of L-BAIBA overlap as potential targets other than the monoamine receptors of clozapine. However, the direct binding of clozapine to these aminoacidic transmitter/modulator receptors remains to be clarified. Therefore, to explore the contribution of increased L-BAIBA on the clinical action of clozapine, this study determined the effects of clozapine and L-BAIBA on tripartite synaptic transmission, including GABAB-R and the group-III metabotropic glutamate receptor (III-mGluR) using cultured astrocytes, as well as on the thalamocortical hyper-glutamatergic transmission induced by impaired glutamate/NMDA receptors using microdialysis. Clozapine increased astroglial L-BAIBA synthesis in time/concentration-dependent manners. Increased L-BAIBA synthesis was observed until 3 days after clozapine discontinuation. Clozapine did not directly bind III-mGluR or GABAB-R, whereas L-BAIBA activated these receptors in the astrocytes. Local administration of MK801 into the reticular thalamic nucleus (RTN) increased L-glutamate release in the medial frontal cortex (mPFC) (MK801-evoked L-glutamate release). Local administration of L-BAIBA into the mPFC suppressed MK801-evoked L-glutamate release. These actions of L-BAIBA were inhibited by antagonists of III-mGluR and GABAB-R, similar to clozapine. These in vitro and in vivo analyses suggest that increased frontal L-BAIBA signaling likely plays an important role in the pharmacological actions of clozapine, such as improving the effectiveness of treating treatment-resistant schizophrenia and several clozapine discontinuation syndromes via the activation of III-mGluR and GABAB-R in the mPFC.

Broiler Heart Muscle Monoaminergic Receptors Alteration in Response to Chronic Heat Stress: Based on Transcription Analysis

Chronic heat stress affects numerous physiological and behavioral mechanisms. Epigenetic changes following prolonged cyclic heat stress, creating new opportunities for molecular biology research. One of these changes involves monoamines, such as serotonin, epinephrine, norepinephrine, dopamine, and their transmission. Broiler chickens are highly susceptible to heat stress, and their hearts become insufficient during the growth phase, leading to hypertrophy of the left heart. RNA-seq data were obtained from NCBI with accession number SRP082125. The expression level of genes was determined with DESeq2 packages. Gene Ontology qualification, including biological processes, cellular components, and molecular role (MF), was performed from the Gene Ontology Resource. Cyclic heat stress in broilers significantly altered monoamine receptor expression. Twenty-nine genes of the monoamine pathway changed their expression in the left heart. Significant downregulation of expression was statistically associated with the ADRB1, HTR2A, and PNMT genes and upregulation of the MAOA gene (P&lt;0.01). STRING database was used to construct the protein-protein interaction network; based on network analysis, the HTR2C, HTR2A, and HTR5A genes were identified as the major nodal genes in the network followed by MAOA, DRD2, DRD5, HTR1B, DRD1, DRD3, and HTR2B genes occupying the second important place in the network module. In conclusion, heat stress treatment prevented cardiac hypertrophy and altered the expression of monoamine genes. This would imply that monoamine transmission plays an important role in the development of cardiac hypertrophy, and that cyclic-chronic heat treatment modulates the cardiac monoaminergic system. These molecular biomarkers could be useful for screening, diagnosis, and treatment of cardiac hypertrophy.

Therapeutic Potential and Limitation of Serotonin Type 7 Receptor Modulation.

Although a number of mood-stabilising atypical antipsychotics and antidepressants modulate serotonin type 7 receptor (5-HT7), the detailed contributions of 5-HT7 function to clinical efficacy and pathophysiology have not been fully understood. The mood-stabilising antipsychotic agent, lurasidone, and the serotonin partial agonist reuptake inhibitor, vortioxetine, exhibit higher binding affinity to 5-HT7 than other conventional antipsychotics and antidepressants. To date, the initially expected rapid onset of antidepressant effects-in comparison with conventional antidepressants or mood-stabilising antipsychotics-due to 5-HT7 inhibition has not been observed with lurasidone and vortioxetine; however, several clinical studies suggest that 5-HT7 inhibition likely contributes to quality of life of patients with schizophrenia and mood disorders via the improvement of cognition. Furthermore, recent preclinical studies reported that 5-HT7 inhibition might mitigate antipsychotic-induced weight gain and metabolic complication by blocking other monoamine receptors. Further preclinical studies for the development of 5-HT7 modulation against neurodevelopmental disorders and neurodegenerative diseases have been ongoing. To date, various findings from various preclinical studies indicate the possibility that 5-HT7 modifications can provide two independent strategies. The first is that 5-HT7 inhibition ameliorates the dysfunction of inter-neuronal transmission in mature networks. The other is that activation of 5-HT7 can improve transmission dysfunction due to microstructure abnormality in the neurotransmission network-which could be unaffected by conventional therapeutic agents-via modulating intracellular signalling during the neurodevelopmental stage or via loss of neural networks with aging. This review attempts to describe the current and novel clinical applications of 5-HT7 modulation based on preclinical findings.

Brexpiprazole Reduces 5-HT7 Receptor Function on Astroglial Transmission Systems.

Several atypical antipsychotics exert mood-stabilising effects via the modulation of various monoamine receptors and intracellular signallings. Recent pharmacodynamic studies suggested that tripartite synaptic transmission can contribute to the pathophysiology of schizophrenia and mood disorders, their associated cognitive impairment, and several adverse reactions to atypical antipsychotics. Therefore, to explore the mechanisms underlying the antidepressive mood-stabilising and antipsychotic effects of brexpiprazole (Brex), we determined the effects of subchronic administration of therapeutically relevant concentrations/doses of Brex on the protein expression of 5-HT receptors, connexin43, cAMP levels, and intracellular signalling in cultured astrocytes and rat hypothalamus using ultra-high-pressure liquid chromatography with mass spectrometry and capillary immunoblotting systems. Subchronic administration of a therapeutically relevant concentration of Brex (300 nM) downregulated both 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors, in addition to phosphorylated Erk (pErk), without affecting phosphorylated Akt in the astroglial plasma membrane. Subchronic administration of 300 nM Brex decreased and increased phosphorylated AMPK and connexin43, respectively, in the astroglial cytosol fraction. A therapeutically relevant concentration of Brex acutely decreased the astroglial cAMP level, whereas, under the inhibition of 5-HT1AR, Brex did not affect astroglial cAMP levels. However, the 5-HT7R-agonist-induced increased astroglial cAMP level was inhibited by Brex. In contrast to the in vitro study, systemic subchronic administration of effective doses of Brex (3 and 10 mg/kg/day for 14 days) increased the cAMP level but did not affect phosphorylated AMPK in the rat hypothalamus. These results suggest several complicated pharmacological features of Brex. Partial 5-HT1AR agonistic action predominates in the low range of therapeutically relevant concentrations of Brex, whereas in the high range, 5-HT7R inverse agonist-like action is overlapped on the 5-HT1A agonistic action. These unique suppressive effects of Brex on 5-HT7R play important roles in the clinical features of Brex regarding its antidepressive mood-stabilising actions.

Differential effects of acute and chronic antagonist and an irreversible antagonist treatment on cocaine self-administration behavior in rats

According to pharmacological theory, the magnitude of an agonist-induced response is related to the number of receptors occupied. If there is a receptor reserve, when the number of receptors is altered the fractional occupancy required to maintain this set number of receptors will change. Therefore, any change in dopamine receptor number will result in a change in the concentration of cocaine required to induce the satiety response. Rats that self-administered cocaine were treated with the irreversible monoamine receptor antagonist, EEDQ, or were infused continuously for 14 days with the D1-like antagonist, SCH23390, treatments known to decrease or increase, respectively, the number of dopamine receptors with a concomitant decrease or increase in response to dopaminergic agonists. The rate of cocaine maintained self-administration increased or decreased in rats treated with EEDQ or withdrawn from chronic SCH23390 infusion, respectively. After EEDQ treatment, the effect ratio of a single dose of SCH23390 or eticlopride were unchanged, indicating that the same SCH23390- and eticlopride-sensitive receptor populations (presumably dopamine) mediated the accelerated cocaine self-administration. Changing the receptor reserve is a key determinant of the rate of cocaine self-administration because the resulting increased or decreased concentration of cocaine results in an accelerated or decelerated rate of cocaine elimination as dictated by first-order kinetics.

Interaction of the preferential D3 agonist (+)PHNO with dopamine D3-D2 receptor heterodimers and diverse classes of monoamine receptor: relevance for PET imaging

(+)-4-Propyl-9-hydroxynaphthoxazine ((+)PHNO) is a high affinity, preferential dopamine D3 versus D2 agonist employed in view of its high specificity and excellent signal-to-noise ratio as a radiotracer for positron emission tomography (PET) imaging. Surprisingly, its profile at other classes of monoamine receptor remains undocumented. In addition to hD3 and hD2L receptors, (+)PHNO revealed high affinity at hD4.4 but not hD1 or hD5 receptors. It also revealed significant affinity for several other G protein-coupled monoaminergic receptors, in particular h5-HT1A and h5-HT7. (+)PHNO behaved as a full agonist at hD4.4 and h5-HT1A receptors with potencies comparable to its actions at hD3 and hD2L receptors, and with less potency at 5-HT7 receptors. In binding assays with membranes derived from cells co-expressing hD3 and hD2L receptors and labeled with [3H]Nemonapride or [3H]Spiperone, the proportion of high affinity binding sites recognized by (+)PHNO was higher than an equivalent mixture of membranes from cells expressing hD3or hD2L receptors, suggesting that (+)PHNO promotes formation of hD3-hD2L heterodimers. Further, in cells co-expressing hD3 and hD2L receptors, (+)PHNO showed higher efficacy for inhibiting forskolin stimulated adenylyl cyclase and inducing adenylyl cyclase super-sensitization than in cells transfected with only hD2L receptors. In conclusion, (+)PHNO is a potent agonist at hD4.4, h5-HT1A and h5-HT7 as well as hD3 and hD2L receptors, and it potently activates dopamine hD3-hD2L heterodimers. These interactions should be considered when interpreting PET studies with [11C](+)PHNO and may be relevant to its functional and potential clinical properties in Parkinson's disease and other disorders.

Depression and Prefrontal Cortex: All Roads Lead to Dopamine

A role for dopamine in the pathophysiology of depression was first proposed in 1975 and reviewed 20 years ago in this journal (1). The results of pharmacological treatment with dopaminergic drugs, however, have been inconclusive. Dopamine agonists such as pramipexole have shown modest clinical efficacy as antidepressants (2), and dopamine-releasing stimulants have either failed in randomized controlled trials or produced small and transient improvements in depressive symptoms (3). Furthermore, more efficacious antidepressants that modulate dopamine release or dopamine receptors also act on other monoamine receptors.

Pharmacological characterization of 3,4-methylenedioxyamphetamine (MDA) analogs and two amphetamine-based compounds: N,α-DEPEA and DPIA

3,4-methylenedioxyamphetamine (MDA) is a psychoactive compound chemically related to the entactogen MDMA. MDA shares some of the entactogenic effects of MDMA but also exerts stimulant effects and psychedelic properties at higher doses. Here, we examined the pharmacological properties of MDA analogs and related amphetamine-based compounds detected in street drug samples or in sport supplements. We examined the key pharmacological mechanisms including monoamine uptake inhibition and release using human embryonic kidney 293 cells stably transfected with the respective human transporters. Additionally, we assessed monoamine transporter and receptor binding and activation properties. MDA, its fluorinated analogs, as well as the α-ethyl containing BDB and the dimeric amphetamine DPIA inhibited NET with the greatest potency and preferentially inhibited 5-HT vs. dopamine uptake. The β‑methoxy MDA analog 3C-BOH and the amphetamine-based N,α-DEPEA inhibited NET and preferentially inhibited dopamine vs. 5-HT uptake. The test drugs mediated efflux of at least one monoamine with the exception of DPIA. Most compounds bound to 5-HT2A and 5-HT2C receptors (Ki ≤ 10 µM) and several substances activated the 5-HT2A and 5-HT2B receptor as partial or full agonists. Furthermore, several compounds interacted with adrenergic receptors and the trace amine-associated receptor 1 (TAAR1) in the micromolar range. The pharmacological profiles of some fluorinated and nonfluorinated MDA analogs resemble the profile of MDMA. In contrast, 3C-BOH and N,α-DEPEA displayed more pronounced dopaminergic activity similar to amphetamine. Pharmacokinetics and pharmacodynamics studies are necessary to better establish the risks and therapeutic potential of the tested drugs.

Impact of 5-HT7 receptor inverse agonism of lurasidone on monoaminergic tripartite synaptic transmission and pathophysiology of lower risk of weight gain

A part of atypical antipsychotics exert mood-stabilising effects via modulation of various monoamine receptors and intracellular signalling. Recent pharmacodynamic studies suggested that tripartite-synaptic transmission can be involved in pathophysiology of mood-disorders, schizophrenia, their associated cognitive impairments, and several adverse-reactions to atypical antipsychotics. Therefore, to explore mechanisms underlying antidepressive mood-stabilising and antipsychotic effects of lurasidone, we determined concentration-dependent effects of acute and subchronic lurasidone administrations on astroglial L-glutamate release, and expression of connexin43, ERK, AKT, adenosine monophosphate activated protein kinase (AMPK), 5-HT1A (5-HT1AR) and 5-HT7 (5-HT7R) receptors in cultured astrocytes using ultra-high-pressure liquid-chromatography with mass-spectrometry and capillary-immunoblotting systems. Therapeutically-relevant lurasidone concentration suppressed astroglial L-glutamate release through activated connexin43-containing hemichannel by decreasing connexin43 expression in plasma-membrane. Subchronic lurasidone administration downregulated 5-HT1AR and 5-HT7R in astroglial plasma-membrane concentration-dependently. Subchronic lurasidone administration attenuated ERK and AMPK signallings concentration-dependently without affecting AKT signalling. These results suggest that effects of subchronic lurasidone administration on astroglial L-glutamate release, 5-HT receptor, and intracellular signalling are similar to vortioxetine and different from mood-stabilising atypical antipsychotics, clozapine. Therefore, inhibitory effects of subchronic lurasidone administration on astroglial L-glutamate release through activated connexin43-containing hemichannel probably contribute to pathophysiology of antidepressive mood-stabilising effects of lurasidone. Furthermore, inhibitory effects of subchronic lurasidone administration on ERK and AMPK activities (without affecting AKT activity) induced by downregulation of 5-HT7R could result in clinical advantages of lurasidone, lower risk of weight gain.

Modulating physicochemical properties of tetrahydropyridine-2-amine BACE1 inhibitors with electron-withdrawing groups: A systematic study

A common challenge for medicinal chemists is to reduce the pKa of strongly basic groups' conjugate acids into a range that preserves the desired effects, usually potency and/or solubility, but avoids undesired effects like high volume of distribution (Vd), limited membrane permeation, and off-target binding to, notably, the hERG channel and monoamine receptors. We faced this challenge with a 3,4,5,6-tetrahydropyridine-2-amine scaffold harboring an amidine, a key structural component of potential inhibitors of BACE1, the rate-limiting enzyme in the production of Aβ species that make up amyloid plaques in Alzheimer's disease. In our endeavor to balance potency with desirable properties to achieve brain penetration, we introduced a diverse set of groups in beta position of the amidine that modulate logD, PSA and pKa. Given the synthetic challenge to prepare these highly functionalized warheads, we first developed a design flow including predicted physicochemical parameters which allowed us to select only the most promising candidates for synthesis. For this we evaluated a set of commercial packages to predict physicochemical properties, which can guide medicinal chemists in their endeavors to modulate pKa values of amidine and amine bases.