Pro-cognitive Properties Research Articles

Gidazepam – daytime tranquilizer for the treatment of anxiety

Gidazepam is a benzodiazepine tranquilizer with several characteristic pharmacodynamic properties: lower affinity to GABAА-receptors than classical benzodiazepines, partial agonism and modulation of GABAА-receptors by stimulation of neurosteroid synthesis through binding to the TranSlocator PrOtein (TSPO), influence on the activity of the serotonergic, dopaminergic and noradrenergic systems. Clinically, Gidazepam is characterized by rapid and sustained anxiolytic, antiasthenic, vegetotropic and procognitive effects. In the lower range of therapeutic doses (20–50 mg/day), the drug has antiasthenic and procognitive properties without subsequent exhaustion; the effects of the upper dose range (from 100–150 mg/day) are closer to the effects of classic benzodiazepine tranquilizers. The drug is well tolerated, it is not characterized by sedation and muscle relaxation, and the risk of addiction or dependence is extremely low.

Novel Leptin-Based Therapeutic Strategies to Limit Synaptic Dysfunction in Alzheimer's Disease.

Accumulation of hyper-phosphorylated tau and amyloid beta (Aβ) are key pathological hallmarks of Alzheimer's disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid β. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.

Effects of an Angiotensin IV Analog on 3-Nitropropionic Acid-Induced Huntington's Disease-Like Symptoms in Rats.

Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, cognitive, and psychiatric dysfunction caused by a mutant huntingtin protein. Compromised metabolic activity resulting from systemic administration of the mitochondrial toxin, 3-nitropropionic acid (3-NP), is known to mimic the pathology of HD and induce HD-like symptoms in rats. N-hexanoic-Tyr-Ile-(6)-amino hexanoic amide (PNB-0408), also known as Dihexa, has been shown to have neuroprotective and procognitive properties in animal models of Alzheimer's and Parkinson's diseases. Given the mechanism of action and success in other neurodegenerative diseases, we felt it an appropriate compound to investigate further for HD. The present study was designed to test if PNB-0408, an angiotensin IV analog, could attenuate 3-NP-induced HD-like symptoms in rats and serve as a potential therapeutic agent. Forty male Wistar rats were randomized into three groups consisting of a "vehicle" group, a "3-NP" group, and a "3-NP + PNB-0408" group. PNB-0408 was administered along with chronic exposure to 3-NP. Animal body weight, motor function, and cognitive abilities were measured for five weeks, before euthanasia and histopathological analysis. Exposure to 3-NP decreased the amount of weight rats gained, impaired spatial learning and memory consolidation, and led to marked motor dysfunction. From our observations and analysis, PNB-0408 did not protect rats from the deficits induced by 3-NP neurotoxicity. Our findings suggest that PNB-0408 may not be an efficacious treatment strategy for preventing 3-NP-induced HD-like symptoms in a preclinical model. These data highlight the need for further research of this compound in alternate models and/or alternative approaches to managing this disorder.

The Natural Protoalkaloid Methyl-2-Amino-3-Methoxybenzoate (MAM) Alleviates Positive as well as Cognitive Symptoms in Rat and Mouse Schizophrenia Models.

The development of new antipsychotics with pro-cognitive properties and less side effects represents a priority in schizophrenia drug research. In this study, we present for the first time a preclinical exploration of the effects of the promising natural atypical antipsychotic Methyl-2-Amino-3- Methoxybenzoate (MAM), a brain-penetrable protoalkaloid from the seed of the plant Nigella damascena. Using animal models related to hyperdopaminergic activity, namely the pharmacogenetic apomorphine (D2/D1 receptor agonist)-susceptible (APO-SUS) rat model and pharmacologically induced mouse and rat models of schizophrenia, we found that MAM reduced gnawing stereotypy and climbing behaviours induced by dopaminergic agents. This predicts antipsychotic activity. In line, MAM antagonized apomorphine-induced c-Fos and NPAS4 mRNA levels in post-mortem brain nucleus accumbens and dorsolateral striatum of APO-SUS rats. Furthermore, phencyclidine (PCP, an NMDA receptor antagonist) and 2,5-Dimethoxy-4-iodoamphetamine (DOI, a 5HT2A/2C receptor agonist) induced prepulse inhibition deficits, reflecting the positive symptoms of schizophrenia, which were rescued by treatment with MAM and atypical antipsychotics alike. Post-mortem brain immunostaining revealed that MAM blocked the strong activation of both PCP- and DOI-induced c-Fos immunoreactivity in a number of cortical areas. Finally, during a 28-day subchronic treatment regime, MAM did not induce weight gain, hyperglycemia, hyperlipidemia or hepato- and nephrotoxic effects, side effects known to be induced by atypical antipsychotics. MAM also did not show any cataleptic effects. In conclusion, its brain penetrability, the apparent absence of preclinical side effects, and its ability to antagonize positive and cognitive symptoms associated with schizophrenia make MAM an exciting new antipsychotic drug that deserves clinical testing.

Superiority of the Triple-Acting 5-HT6R/5-HT3R Antagonist and MAO-B Reversible Inhibitor PZ-1922 over 5-HT6R Antagonist Intepirdine in Alleviation of Cognitive Deficits in Rats.

The multifactorial origin and neurochemistry of Alzheimer's disease (AD) call for the development of multitarget treatment strategies. We report a first-in-class triple acting compound that targets serotonin type 6 and 3 receptors (5-HT-Rs) and monoamine oxidase type B (MAO-B) as an approach for treating AD. The key structural features required for MAO-B inhibition and 5-HT6R antagonism and interaction with 5-HT3R were determined using molecular dynamic simulations and cryo-electron microscopy, respectively. Bioavailable PZ-1922 reversed scopolamine-induced cognitive deficits in the novel object recognition test. Furthermore, it displayed superior pro-cognitive properties compared to intepirdine (a 5-HT6R antagonist) in the AD model, which involved intracerebroventricular injection of an oligomeric solution of amyloid-β peptide (oAβ) in the T-maze test in rats. PZ-1922, but not intepirdine, restored levels of biomarkers characteristic of the debilitating effects of oAβ. These data support the potential of a multitarget approach involving the joint modulation of 5-HT6R/5-HT3R/MAO-B in AD.

Synthesis, biological evaluation, and molecular modeling of ORM-10921 and its analogs as α2C -adrenoceptor antagonists.

The α2C -adrenoceptor (α2C -AR) is regarded as one of the potential targets for antipsychotics. A few of structurally diverse α2C -AR antagonists have been reported, among which ORM-10921, containing one rigid tetracyclic framework with two neighboring chiral centers, has exhibited remarkable antipsychotic-like effects and pro-cognitive properties in different animal models. Yet the binding mode of ORM-10921 remains elusive. In this study, all of its four stereoisomers and a set of its analogs were synthesized and in vitro evaluated for their α2C -AR antagonist activities. The molecular docking study and hydration site analysis gave a rational explanation for the biological results, which might provide helpful insights into the binding mode and future optimization.

Effect of Low Molecular Weight Nerve Growth Factor Mimetic GK-2 on Cognitive Function and Synaptic Transmission in Hippocampal Slices

Nerve growth factor (NGF) contributes to the proliferation, differentiation and maintenance of the viability and functioning of peripheral and central neurons. At the Research Zakusov Institute of Pharmacology a dimeric dipeptide mimetic of the NGF loop 4 bis(monosuccinyl-L-glutamyl-L-lysine) hexamethylenediamide (GK-2) was created. GK-2 activates PI3K/AKT and PLC-γ1 signaling cascades, without affecting MAPK/ERK, and appears to have procognitive properties. In the present study, we investigated the mnemotropic effects of GK-2 with a single intraperitoneal dose of 0.1, 0.5 and 5.0 mg/kg in the novel object recognition test in rats. GK-2 at a dose of 0.5 mg/kg statistically significantly improved the long-term memory of animals. In experiments on the rat hippocampal acute slices, we evaluated the effects of GK-2 on synaptic transmission and its plastic properties in the synaptic system Schaffer collaterals − CA1 pyramidal cell.

Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice.

Depression, anxiety, and schizophrenia may coexist in psychiatric patients. Moreover, these disorders are very often associated with cognitive impairments. However, pharmacotherapy of these conditions remains challenging due to limited drug effectiveness or numerous side effects. Therefore, there is an urgent need to develop novel multimodal compounds that can be used to treat depression, anxiety, and schizophrenia, as well as memory deficits. Thus, this study aimed to evaluate the potential antidepressant-like, anxiolytic-like, antipsychotic-like effects, and anti-amnesic properties, of the novel arylpiperazine derivative of salicylamide, JJGW07, with an affinity towards serotonin 5-HT1A, 5-HT2A, and 5-HT7 and dopamine D2 receptors. Firstly, we investigated the compound's affinity for 5-HT6 receptors and its functional activity by using in vitro assays. JJGW07 did not bind to 5-HT6 receptors and showed antagonistic properties for 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors. Based on the receptor profile, we performed behavioral studies in mice to evaluate the antidepressant-like, anxiolytic-like, and antipsychotic-like activity of the tested compound using forced swim and tail suspension tests; four-plate, marble-burying, and elevated plus maze tests; and MK-801- and amphetamine-induced hyperlocomotion tests, respectively. JJGW07 revealed antidepressant-like properties in the tail suspension test, anxiolytic-like effects in the four-plate and marble-burying tests, and antipsychotic-like activity in the MK-801-induced hyperlocomotion test. Importantly, the tested compound did not induce catalepsy and motor impairments or influence locomotor activity in rodents. Finally, to assess the potential procognitive and anti-amnesic properties of JJGW07, we used passive avoidance and object recognition tests in mice. JJGW07 demonstrated positive effects on long-term emotional memory and also ameliorated MK-801-induced emotional memory impairments in mice, but showed no procognitive properties in the case of recognition memory. Our results encourage the search for new compounds among salicylamide derivatives, which could be model structures with multitarget mechanisms of action that could be used in psychiatric disorder therapy.

Evaluation of the Effect of Cariprazine on Memory and Cognition in Experimental Rodent Models.

The main symptoms of schizophrenia are categorized as positive, negative, and cognitive. Cognitive impairments do not generally respond to antipsychotics. Cariprazine is a novel antipsychotic conceived with the idea that high affinity for D3 receptors may elicit a favorable response in the management of cognitive deficits. We evaluated the pro-cognitive properties of 14-day long pre-treatment with cariprazine (0.25, 0.5, and 1 mg/kg b.w. intraperitoneally) in experimental rodent models with scopolamine-induced memory impairment employing novel object recognition test (NORT), T-maze, Y-maze, and passive avoidance tasks (step-through and step-down). Statistical analysis was performed with One Way ANOVA. In NORT cariprazine increased the recognition index. In T-maze and Y-maze cariprazine increased the working memory index as well as the percentage of spontaneous alternation. Cariprazine improved learning and memory in both short-term and long-term memory retention tests in step-down and step-through tasks. Cariprazine improves learning, recognition, and spatial memory in rats with scopolamine-induced memory impairment. Cariprazine's beneficial effect on cognition is likely due to its affinity for D3 receptors, as well as agonism at 5-HT1A receptors. Most probably, the cognitive-enhancing properties of cariprazine are the result of integrated modulation in the amygdala, hippocampus, and prefrontal cortex.

Neuroprotective and anti-epileptic potentials of genus Artemisia L.

The Genus Artemisia L. is one of the largest genera in the Asteraceae family growing wild over in Europe, North America, and Central Asia and has been widely used in folk medicine for the treatment of various ailments. Phytochemical and psychopharmacological studies indicated that the genus Artemisia extracts contain various antioxidant and anti-inflammatory compounds and possess antioxidant, anti-inflammatory, antimicrobial, antimalarial, and antitumor activity. Recently, increasing experimental studies demonstrated that many Artemisia extracts offer a great antiepileptic potential, which was attributed to their bioactive components via various mechanisms of action. However, detailed literature on the antiepileptic properties of the genus Artemisia and its mechanism of action is segregated. In this review, we tried to gather the detailed neuroprotective and antiepileptic properties of the genus Artemisia and its possible underlying mechanisms. In this respect, 63 articles were identified in the PubMed and Google scholars databases, from which 18 studies were examined based on the pharmacological use of the genus Artemisia species in epilepsy. The genus Artemisia extracts have been reported to possess antioxidant, anti-inflammatory, neurotransmitter-modulating, anti-apoptotic, anticonvulsant, and pro-cognitive properties by modulating oxidative stress caused by mitochondrial ROS production and an imbalance of antioxidant enzymes, by protecting mitochondrial membrane potential required for ATP production, by upregulating GABA-A receptor and nACh receptor activities, and by interfering with various anti-inflammatory and anti-apoptotic signaling pathways, such as mitochondrial apoptosis pathway, ERK/CREB/Bcl-2 pathway and Nrf2 pathway. This review provides detailed information about some species of the genus Artemisia as potential antiepileptic agents. Hence, we recommend further investigations on the purification and identification of the most biological effective compounds of Artemisia and the mechanisms of their action to cure epilepsy and other neurological diseases.

New β-arylchalcogeno amines with procognitive properties targeting Carbonic Anhydrases and Monoamine Oxidases

Cognitive deficits are enduring and disabling symptoms for many patients with severe mental illness, and these impairments are inadequately addressed by current medications. In this study, we reported the synthesis of β-arylchalcogeno amines bearing sulfurated, selenated, and tellurated moieties (2–4) which are structurally related to amphetamine with good activation properties for Carbonic Anhydrases (CAs) isoforms present in the cortical and hippocampal brain structures (hCA IV and hCA XIV). In addition, these compounds showed selective inhibition against the Monoamine oxidase (MAO) A isoform. In vivo evaluation of two derivatives (2a and 3a) revealed procognitive effects in the object recognition and social discrimination tests. Interestingly, these compounds, despite having a similar structure to amphetamine, did not caused hypophagia or hyperlocomotion, two effects often observed following the administration of amphetamine-like drugs. In this context, β-arylchalcogeno amines may have utility for improving the symptoms of cognitive decline associated with neurodegenerative and psychiatric diseases such as attention deficit disorder, Parkinson's disease-related cognitive dysfunction and cognitive disorders associated with depression.

Modulation of the mammalian GABAA receptor by type I and type II positive allosteric modulators of the α7 nicotinic acetylcholine receptor.

Positive allosteric modulators of the α7 nicotinic acetylcholine (nACh) receptor (α7-PAMs) possess promnesic and procognitive properties and have potential in the treatment of cognitive and psychiatric disorders including Alzheimer's disease and schizophrenia. Behavioural studies in rodents have indicated that α7-PAMs can also produce antinociceptive and anxiolytic effects that may be associated with positive modulation of the GABAA receptor. The overall goal of this study was to investigate the modulatory actions of selected α7-PAMs on the GABAA receptor. We employed a combination of cell fluorescence imaging, electrophysiology, functional competition and site-directed mutagenesis to investigate the functional and structural mechanisms of modulation of the GABAA receptor by three representative α7-PAMs. We show that the α7-PAMs at micromolar concentrations enhance the apparent affinity of the GABAA receptor for the transmitter and potentiate current responses from the receptor. The compounds were equi-effective at binary αβ and ternary αβγ GABAA receptors. Functional competition and site-directed mutagenesis indicate that the α7-PAMs bind to the classic anaesthetic binding sites in the transmembrane region in the intersubunit interfaces, which results in stabilization of the active state of the receptor. We conclude that the tested α7-PAMs are micromolar-affinity, intermediate- to low-efficacy allosteric potentiators of the mammalian αβγ GABAA receptor. Given the similarities in the in vitro sensitivities of the α7 nACh and α1β2γ2L GABAA receptors to α7-PAMs, we propose that doses used to produce nACh receptor-mediated behavioural effects in vivo are likely to modulate GABAA receptor function.

Effect of Concurrent Use of Memantine on the Efficacy of Masupirdine (SUVN-502): A Post Hoc Analysis of a Phase2 Randomized Placebo-Controlled Study.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive deterioration in cognition, memory and activities of daily living. Selective blockade of serotonin-6 (5-HT6) receptors, which are exclusively localized to the central nervous system, is reported to play an important role in learning and memory. Masupirdine is a potent and selective 5-HT6 receptor antagonist with pro-cognitive properties in animal models of cognition. The efficacy and safety of masupirdine were evaluated in patients with moderate AD concurrently treated with donepezil and memantine. A total of 564 patients were randomized in a 1:1:1 ratio. The study consisted of a 26-week double-blind treatment period. The primary efficacy outcome was the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog 11). Changes from baseline were analyzed using a mixed effects model for repeated measures (MMRM). In exploratory post hoc analyses, patients were subdivided based on the use of memantine dosage forms and memantine plasma concentrations, to evaluate the impact of memantine on the efficacy of masupirdine. In an exploratory post hoc analysis, less worsening in cognition (ADAS-Cog 11 scores) was observed with masupirdine treatment as compared with placebo in patients whose trough memantine plasma concentrations were ≤ 100ng/mL. Although prespecified study endpoints of the phase2 study were not met, these exploratory post hoc subgroup observations are hypothesis-generating and suggest that the efficacy of masupirdine was adversely affected by concurrent therapy with memantine. Further assessment of masupirdine to determine its potential role as a treatment option for cognitive deficits associated with AD is warranted. The study was registered at ClinicalTrials.gov (NCT02580305).

Muscarinic Acetylcholine Receptor Agonists as Novel Treatments for Schizophrenia

Schizophrenia remains a challenging disease to treat effectively with current antipsychotic medications due to their limited efficacy across the entire spectrum of core symptoms as well as their often burdensome side-effect profiles and poor tolerability. An unmet need remains for novel, mechanistically unique, and better tolerated therapeutic agents for treating schizophrenia, especially those that treat not only positive symptoms but also the negative and cognitive symptoms of the disease. Almost 25 years ago, the muscarinic acetylcholine receptor (mAChR) agonist xanomeline was reported to reduce psychotic symptoms and improve cognition in patients with Alzheimer's disease. The antipsychotic and procognitive properties of xanomeline were subsequently confirmed in a small study of acutely psychotic patients with chronic schizophrenia. These unexpected clinical findings have prompted considerable efforts across academia and industry to target mAChRs as a new approach to potentially treat schizophrenia and other psychotic disorders. The authors discuss recent advances in mAChR biology and pharmacology and the current understanding of the relative roles of the various mAChR subtypes, their downstream cellular effectors, and key neural circuits mediating the reduction in the core symptoms of schizophrenia in patients treated with xanomeline. They also provide an update on the status of novel mAChR agonists currently in development for potential treatment of schizophrenia and other neuropsychiatric disorders.

Dual 5-HT3 and 5-HT6 Receptor Antagonist FPPQ Normalizes Phencyclidine-Induced Disruption of Brain Oscillatory Activity in Rats.

Schizophrenia is a severe mental disorder featuring psychotic, depressive, and cognitive alterations. Current antipsychotic drugs preferentially target dopamine D2-R and/or serotonergic 5-HT2A/1A-R. They partly alleviate psychotic symptoms but fail to treat negative symptoms and cognitive deficits. Here we report on the putative antipsychotic activity of (1-[(3-fluorophenyl)sulfonyl]-4-(piperazin-1-yl)-1H-pyrrolo[3,2-c]quinoline dihydrochloride) (FPPQ), a dual serotonin 5-HT3-R/5-HT6-R antagonist endowed with pro-cognitive properties. FPPQ fully reversed phencyclidine-induced decrease of low-frequency oscillations in the medial prefrontal cortex of anaesthetized rats, a fingerprint of antipsychotic activity. This effect was mimicked by the combined administration of the 5-HT3-R and 5-HT6-R antagonists ondansetron and SB-399 885, respectively, but not by either drug alone. In freely moving rats, FPPQ countered phencyclidine-induced hyperlocomotion and augmentation of gamma and high-frequency oscillations in medial prefrontal cortex, dorsal hippocampus, and nucleus accumbens. Overall, this supports that simultaneous blockade of 5-HT3R and 5-HT6-R-like that induced by FPPQ-can be a new target in antipsychotic drug development.

Lurasidone-induced tardive dyskinesia

<br>Lurasidone is a novel atypical antipsychotic with additional antidepressant and pro-cognitive properties. The drug has shown good efficacy in treatment of schizophrenia as well as bipolar disorder. It is currently used as monotherapy as well as adjunctive therapy with Lithium or valproate, due to its lower propensity of cardiometabolic side effects and endocrinological adverse effects. Extra pyramidal side effects and akathisia with lurasidone therapy are reported in a minority of patients, but very few instances of tardive dyskinesia with lurasidone therapy are reported so far.<br>

Structure-Based Design and Optimization of FPPQ, a Dual-Acting 5-HT3 and 5-HT6 Receptor Antagonist with Antipsychotic and Procognitive Properties.

In line with recent clinical trials demonstrating that ondansetron, a 5-HT3 receptor (5-HT3R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT6 receptor (5-HT6R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT3/5-HT6R antagonists. We identified the first-in-class compound FPPQ, which behaves as a 5-HT3R antagonist and a neutral antagonist 5-HT6R of the Gs pathway. FPPQ shows selectivity over 87 targets and decent brain penetration. Likewise, FPPQ inhibits phencyclidine (PCP)-induced hyperactivity and displays procognitive properties in the novel object recognition task. In contrast to FPPQ, neither 5-HT6R inverse agonist SB399885 nor neutral 5-HT6R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT3R antagonism and 5-HT6R antagonism, exemplified by FPPQ, contributes to alleviating the positive-like symptoms. Present findings reveal critical structural features useful in a rational polypharmacological approach to target 5-HT3/5-HT6 receptors and encourage further studies on dual-acting 5-HT3/5-HT6R antagonists for the treatment of psychiatric disorders.

The selective TAAR1 partial agonist RO5263397 promoted novelty recognition memory in mice

Trace amine-associated receptor 1 (TAAR1) is a G protein-coupled receptor that has a particular role in regulating dopaminergic, serotonergic, and glutamatergic transmission. TAAR1 agonists have shown pro-cognitive activities. However, it remains largely unknown of the effects of TAAR1 agonists on memory performance. Here, by using the mice novel object recognition (NOR) test, we examined the effects of the selective TAAR1 partial agonist RO5263397 on recognition memory. We found that RO5263397 significantly enhanced the retrieval of short-term memory (STM; 20min after training) both in male and female mice. RO5263397 promoted the retrieval of STM in the wild-type (WT) littermates but not TAAR1-KO mice, indicating that the effects of RO5263397 were dependent on TAAR1. Interestingly, compared to their WT litters, TAAR1-KO mice showed similar levels of STM, suggesting that genetic deletion of taar1 gene did not affect the STM retrieval. Furthermore, RO5263397 also promoted the retrieval of long-term NOR memory (24h after training). These results indicate that TAAR1 activation promotes NOR memory retrieval. Consistent with previous studies, our finding further suggests that TAAR1 agonists have pro-cognitive properties.

Differential effects of alkaloids on memory in rodents

Nicotinic acetylcholine receptors (nAChRs) play a critical role in the neuropharmacology of learning and memory. As such, naturally occurring alkaloids that regulate nAChR activity have gained interest for understanding and potentially improving memory function. In this study, we tested the acute effects of three known nicotinic alkaloids, nicotine, cotinine, and anatabine, in suppressing scopolamine-induced memory deficit in rodents by using two classic memory paradigms, Y-maze and novel object recognition (NOR) in mice and rats, respectively. We found that all compounds were able to suppress scopolamine-induced spatial memory deficit in the Y-maze spontaneous alternation paradigm. However, only nicotine was able to suppress the short-term object memory deficit in NOR, despite the higher doses of cotinine and anatabine used to account for their potential differences in nAChR activity. These results indicate that cotinine and anatabine can uniquely regulate short-term spatial memory, while nicotine seems to have more robust and general role in memory regulation in rodents. Thus, nAChR-activating alkaloids may possess distinct procognitive properties in rodents, depending on the memory types examined.

2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT6 Receptor Inverse Agonists with Cognition-Enhancing Activity.

Serotonin type 6 receptor (5-HT6R) has gained particular interest as a promising target for treating cognitive deficits, given the positive effects of its antagonists in a wide range of memory impairment paradigms. Herein, we report on degradation of the 1H-pyrrolo[3,2-c]quinoline scaffold to provide the 2-phenyl-1H-pyrrole-3-carboxamide, which is devoid of canonical indole-like skeleton and retains recognition of 5-HT6R. This modification has changed the compound’s activity at 5-HT6R-operated signaling pathways from neutral antagonism to inverse agonism. The study identified compound 27 that behaves as an inverse agonist of the 5-HT6R at the Gs and Cdk5 signaling pathways. Compound 27 showed high selectivity and metabolic stability and was brain penetrant. Finally, 27 reversed scopolamine-induced memory decline in the novel object recognition test and exhibited procognitive properties in the attentional set-shifting task in rats. In light of these findings, 27 might be considered for further evaluation as a new cognition-enhancing agent, while 2-phenyl-1H-pyrrole-3-carboxamide might be used as a template for designing 5-HT6R inverse agonists.