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Following the glutamatergic theory of schizophrenia and based on our previous study regarding the antipsychotic-like activity of mGlu7 NAMs, we synthesized a new compound library containing 103 members, which were examined for NAM mGlu7 activity in the T-REx 293 cell line expressing a recombinant human mGlu7 receptor. Out of the twenty-two scaffolds examined, active compounds were found only within the quinazolinone chemotype. 2-(2-Chlorophenyl)-6-(2,3-dimethoxyphenyl)-3-methylquinazolin-4(3H)-one (A9-7, ALX-171, mGlu7 IC50 = 6.14 µM) was selective over other group III mGlu receptors (mGlu4 and mGlu8), exhibited satisfactory drug-like properties in preliminary DMPK profiling, and was further tested in animal models of antipsychotic-like activity, assessing the positive, negative, and cognitive symptoms. ALX-171 reverse DOI-induced head twitches and MK-801-induced disruptions of social interactions or cognition in the novel object recognition test and spatial delayed alternation test. On the other hand, the efficacy of the compound was not observed in the MK-801-induced hyperactivity test or prepulse inhibition. In summary, the observed antipsychotic activity profile of ALX-171 justifies the further development of the group of quinazolin-4-one derivatives in the search for a new drug candidate for schizophrenia treatment. [ABSTRACT FROM AUTHOR]

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu4 receptor positive allosteric modulatory activity (EC50 = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu1, mGlu2 and mGlu5 receptors, but modulated mGlu7 and mGlu8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators (34, 37, 52, 60 and 62) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide (62), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu4 PAM ADX88178. [ABSTRACT FROM AUTHOR]

Currently used antidepressants do not always provide the desired results, and many patients suffer from treatment-resistant depression. Clinical studies suggest that zinc deficiency (ZnD) may be an important risk factor for depression and might blunt the effect of antidepressants. This study aimed to examine whether ZnD might blunt the effectiveness of antidepressants in the olfactory bulbectomy model (OB) of depression in rats. For this purpose, rats were subjected to the OB model, fed a zinc-deficient diet (3 mg Zn/kg) for 3 weeks, and finally treated with escitalopram (Esc), venlafaxine (Ven) 10 mg/kg, i.p., or combined Esc/Ven (1 mg/kg, i.p.) with zinc (5 mg/kg) for another 3 weeks. Open field (OFT), forced swim (FST), and sucrose intake (SIT) tests were used to evaluate depressive-like behavioral changes. In addition, serum, intracellular, and synaptic Zn concentrations and the level of zinc transporter (ZnT) proteins were analyzed. The OB + ZnD model induced hyperactivity in rats in the OFT, increased immobility time in the FST, and anhedonia in the SIT. Chronic treatment with Esc reduced immobility time in the FST in the OB + ZnD model. Esc/Ven +Zn increased sucrose intake in rats from the OB + ZnD group. The OB + ZnD decreased serum zinc levels and intracellular and synaptic Zn concentration in the prefrontal cortex (PFC) and cerebellum. These changes were normalized by chronic administration of Esc/Ven +Zn. Moreover, OB + ZnD decreased levels of the ZnT1 protein in the PFC and Hp and ZnT3 in Hp. Chronic administration of antidepressants did not alter the levels of ZnT proteins. The OB + ZnD model induces more depressive-like effects than either model alone. Our results show that ZnD may induce drug resistance in rats. Normalizing serum or brain zinc concentration is insufficient to reverse behavioral abnormalities caused by the OB + ZnD model. However, zinc supplementation might improve the effectiveness of antidepressants in reversing particular depression symptoms. [ABSTRACT FROM AUTHOR]

The present study reports for the first time the occurrence of selected pharmaceuticals and personal care products (PPCPs) in the shallow aquifer underlying the Kraków city. Urban groundwater samples were gathered from 11 wells, which can serve as the emergency water supply wells. Liquid chromatography with tandem mass spectrometry method with the previous pre-concentration of samples using an SPE technique was applied for the determination of the PPCPs selected. There were quantified concentrations of PPCPs from the groups of estrogens (17-α-ethinylestradiol (EE2), 2.6–18.7 ng/L), non-steroidal anti-inflammatory drugs (ketoprofen, 59.5 ng/L in 1 sample), and antimicrobial preservatives used in cosmetic production (methylparaben up to 91.5 ng/L). Triclosan was observed in all analysed water samples in concentrations above the limit of detection. The presence of the PPCPs in the shallow aquifer is an evidence that the sewer network system under the city leaks and then pollutes the urban groundwater. [ABSTRACT FROM AUTHOR]

Background and Purpose: The concept of opioid ligands biased towards the G protein pathway with minimal recruitment of β-arrestin-2 is a promising approach for the development of novel, efficient, and potentially nonaddictive opioid therapeutics. A recently discovered biased μ-opioid receptor agonist, PZM21, showed analgesic effects with reduced side effects. Here, we aimed to further investigate the behavioural and biochemical properties of PZM21.Experiment Approach: We evaluated antinociceptive effects of systemic and intrathecal PZM21 administration. Its addiction-like properties were determined using several behavioural approaches: conditioned place preference, locomotor sensitization, precipitated withdrawal, and self-administration. Also, effects of PZM21 on morphine-induced antinociception, tolerance, and reward were assessed. Effects of PZM21 on striatal release of monoamines were evaluated using brain microdialysis.Key Results: PZM21 caused long-lasting dose-dependent antinociception. It did not induce reward- and reinforcement-related behaviour; however, its repeated administration led to antinociceptive tolerance and naloxone-precipitated withdrawal symptoms. Pretreatment with PZM21 enhanced morphine-induced antinociception and attenuated the expression of morphine reward. In comparison to morphine, PZM21 administration induced a moderate release of dopamine and a robust release of 5-HT in the striatum.Conclusions and Implications: PZM21 exhibited antinociceptive efficacy, without rewarding or reinforcing properties. However, its clinical application may be restricted, as it induces tolerance and withdrawal symptoms. Notably, its ability to diminish morphine reward implies that PZM21 may be useful in treatment of opioid use disorders. [ABSTRACT FROM AUTHOR]

Purpose: Like other psychedelics, D-lysergic acid diethylamide (LSD) affects numerous serotonin receptors, and according to the current dogma, the 5-HT2A receptors are considered the main target for its hallucinogenic effects. LSD, however, also displays agonistic activity at the 5-HT5A receptors, which mediate some of LSD-induced behavioural effects.Methods: Using male Sprague Dawley rats, we examined the effects of 5-HT2A and 5-HT5A receptor antagonists on LSD-induced stimulus control in the two-lever drug discrimination test using a FR10 schedule of reinforcement.Results: In animals trained to discriminate 0.08 mg/kg LSD from vehicle 15 minutes after injection, LSD produced dose-related increases in response, with an ED50 (±95% confidence limits) of 0.0384 (± 0.025-0.051) mg/kg). LSD-like responses were observed when the training dose of LSD was given 5-30 but not 90 minutes before the test. Confirming earlier reports, the 5-HT antagonist ketanserin (2 mg/kg) attenuated the LSD response in 50% of rats, and due to pretreatment with 0.2 and 2 mg/kg MDL 100907, 63% and 67% of animals, respectively, failed to select the LSD lever. We then investigated the effects of two 5-HT5A receptor antagonists, and we found that 56% and 60% of rats pretreated with 3 and 10 mg/kg SB 699551, respectively, failed to select the LSD lever. Due to pretreatment with 0.01 mg/kg ASP 5736, 58% of rats did not select the LSD lever. This dose also reduced the response rate but not the number of rats failing to complete the test.Conclusions: The present results suggest that antagonists of the 5-HT5A receptor may inhibit subjective effects of LSD in rats. [ABSTRACT FROM AUTHOR]

A growing body of evidence points out the involvement of the µ-opioid receptors in the modulation of stress-related behaviour. It has been suggested that µ-opioid receptor agonists may attenuate behavioural despair following animals' exposure to an acute, inescapable stressor. Moreover, morphine was shown to ameliorate fear memories caused by a traumatic experience. As typical µ-opioid receptor agonists entail a risk of serious side effects and addiction, novel, possibly safer and less addictive agonists of this receptor are currently under investigation. One of them, PZM21, preferentially acting via the G protein signalling pathway, was previously shown to be analgesic, but less addictive than morphine. Here, we aimed to further test this ligand in stress-related behavioural paradigms in mice. The study has shown that, unlike morphine, PZM21 does not decrease immobility in the forced swimming and tail suspension tests. On the other hand, we observed that both mice treated with PZM21 and those receiving morphine presented a slight attenuation of freezing across the consecutive fear memory retrievals in the fear conditioning test. Therefore, our study implies that at the range of tested doses, PZM21, a nonrewarding representative of G protein-biased µ-opioid receptor agonists, may interfere with fear memory consolidation while having no beneficial effects on behavioural despair in mice. • PZM21 (a nonrewarding µ-OR agonist) does not diminish behavioural despair. • PZM21 causes a moderate decrease in conditioned fear response. • Morphine appears to be effective in both conditions. [ABSTRACT FROM AUTHOR]

Objectives To determine the ability of 11 sildenafil analogues to discriminate between cyclic nucleotide phosphodiesterases (cn PDEs) and to characterise their inhibitory potencies ( Ki values) of PDE5A1-dependent guanosine cyclic monophosphate ( cGMP) hydrolysis. Methods Sildenafil analogues were identified by virtual ligand screening ( VLS) and screened for their ability to inhibit adenosine cyclic monophosphate ( cAMP) hydrolysis by PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2, and cGMP hydrolysis by PDE5A, PDE6C, PDE9A2 for a low (1 n m) and high concentration (10 μ m). Complete IC50 plots for all analogues were performed for PDE5A-dependent cGMP hydrolysis. Docking studies and scoring were made using the ICM molecular modelling software. Key findings The analogues in a low concentration showed no or low inhibition of PDE1A1, PDE1B1, PDE2A1, PDE3A, PDE10A1 and PDE10A2. In contrast, PDE5A and PDE6C were markedly inhibited to a similar extent by the analogues in a low concentration, whereas PDE9A2 was much less inhibited. The analogues showed a relative narrow range of Ki values for PDE5A inhibition (1.2-14 n m). The sildenafil molecule was docked in the structure of PDE5A1 co-crystallised with sildenafil. All the analogues had similar binding poses as sildenafil. Conclusions Sildenafil analogues that inhibit cellular cGMP efflux are potent inhibitors of PDE5A and PDE6C. [ABSTRACT FROM AUTHOR]

Abstract: Structure–activity relationships of a series of bis-arylic compounds, investigated as 5-HT7R ligands, are reported. The main structural modifications involved a central aryl moiety (phenyl, pyridine, diazine, triazine) and the nature and position of an amine-containing aliphatic chain. The affinity of the synthesized compounds (26nM–10μM) was systematically correlated with other previously reported series of bis-arylic ligands and rationalized by a ligand-based pharmacophore approach. [Copyright &y& Elsevier]

Among different approaches to the search for novel—safer and less addictive—opioid analgesics, biased agonism has received the most attention in recent years. Some μ-opioid receptor agonists with G protein bias, including SR compounds, were proposed to induce diminished side effects. However, in many aspects, behavioral effects of those compounds, as well as the mechanisms underlying differences in their action, remain unexplored. Here, we aimed to evaluate the effects of SR-14968 and SR-17018, highly G protein-biased opioid agonists, on antinociception, motor activity and addiction-like behaviors in C57BL/6J mice. The obtained results showed that the compounds induce strong and dose-dependent antinociception. SR-14968 causes high, and SR-17018 much lower, locomotor activity. Both agonists develop reward-associated behavior and physical dependence. The compounds also cause antinociceptive tolerance, however, developing more slowly when compared to morphine. Interestingly, SR compounds, in particular SR-17018, slow down the development of antinociceptive tolerance to morphine and inhibit some symptoms of morphine withdrawal. Therefore, our results indicate that SR agonists possess rewarding and addictive properties, but can positively modulate some symptoms of morphine dependence. Next, we have compared behavioral effects of SR-compounds and PZM21 and searched for a relationship to the substantial differences in molecular interactions that these compounds form with the µ-opioid receptor. [ABSTRACT FROM AUTHOR]

Abstract: New, flexible (7, 9, 11 and 13) and rigid (8, 10, 12 and 14) imides with a 1-(m-trifluorophenyl)piperazine fragment and a tetramethylene or a 1e,4e-cyclohexylene spacer, respectively, showed very high affinity (K i =0.3–34nM) and agonistic in vivo activity for 5-HT1A receptors. Flexible new compounds and the previously described 5 also bound to 5-HT7 receptors (K i =21–134nM). Selected glutarimide derivatives, that is, the most potent postsynaptic 5-HT1A receptor agonist rigid compound 8 and its flexible analogue 7, as well as the previously described full agonist—rigid compound 6 and the partial agonist—its flexible counterpart 5 exhibited moderate affinity for α1-adrenoceptors (K i =85–268nM), but were practically devoid of any affinity for dopamine D2 sites. Those glutarimides demonstrated anxiolytic- (5 and 7) and antidepressant-like (5, 6 and 8) activity in the four-plate and the swim tests in mice, respectively; at the same time, however, they inhibited the locomotor activity of mice. The antidepressant-like effect of 8 was significantly stronger than that induced by imipramine used as a reference antidepressant. [Copyright &y& Elsevier]

Six extended analogues of the recently described peptides (LDVL, ADVL) were designed and synthesized on a solid support, and then impregnated on TLC stationary phases. The impact of the impregnated peptide sequence modifications on the chromatographic retard, Δ Rf (difference in the migration of tested compound on control and impregnated plates), of 42 arylpiperazine 5-HT1A receptor ligands was studied. None of the new models tested made a better prediction of 5-HT1A affinity than that utilizing ADVL tetrapeptide. Further validation of the ADVL model on a set of 22 structurally differentiated 2-methoxy-phenylpiperazine derivatives confirmed its effectiveness in the affinity discrimination of a coherent group of 5-HT1A receptor ligands. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Serotonin receptors are extensively examined by academic and industrial researchers, due to their vital roles, which they play in the organism and constituting therefore important drug targets. Up to very recently, it was assumed that the basic nitrogen in compound structure is a necessary component to make it active within this receptor system. Such nitrogen interacts in its protonated form with the aspartic acid from the third transmembrane helix (D3x32) forming a hydrogen bond tightly fitting the ligand in the protein binding site. However, there are several recent studies that report strong serotonin receptor affinity also for compounds without a basic moiety in their structures. In the study, we carried out a comprehensive in silico analysis of the low-basicity phenomenon of the selected serotonin receptor ligands. We focused on the crystallized representatives of the proteins of 5-HT1B, 5-HT2A, 5-HT2B, and 5-HT2C receptors, and examined the problem both from the ligand- and structure-based perspectives. The study was performed for the native proteins, and for D3x32A mutants. The investigation resulted in the determination of nonstandard structural requirements for activity towards serotonin receptors, which can be used in the design of new nonbasic ligands. [ABSTRACT FROM AUTHOR]

Molecular modeling approaches are an indispensable part of the drug design process. They not only support the process of searching for new ligands of a given receptor, but they also play an important role in explaining particular activity pathways of a compound. In this study, a comprehensive molecular modeling protocol was developed to explain the observed activity profiles of selected µ opioid receptor agents: two G protein-biased µ opioid receptor agonists (PZM21 and SR-17018), unbiased morphine, and the β-arrestin-2-biased agonist, fentanyl. The study involved docking and molecular dynamics simulations carried out for three crystal structures of the target at a microsecond scale, followed by the statistical analysis of ligand–protein contacts. The interaction frequency between the modeled compounds and the subsequent residues of a protein during the simulation was also correlated with the output of in vitro and in vivo tests, resulting in the set of amino acids with the highest Pearson correlation coefficient values. Such indicated positions may serve as a guide for designing new G protein-biased ligands of the µ opioid receptor. [ABSTRACT FROM AUTHOR]

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT1A receptor agonist (2R)-(+)-8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro-N-[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT1A receptor agonist (although not alike other 5-HT1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N-Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT1A receptor model and interacted with similar 5-HT1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes. [ABSTRACT FROM AUTHOR]

Abstract: Introduction of 1,4-disubstituted cyclohexane ring in the structure of flexible long chain arylpiperazines resulted in linearly constrained, potent serotonin (5-HT)1A ligands. In order to trace structure–intrinsic activity relationships in this group, a new series of 1-substituted 4-(4-arylpiperazin-1-yl)cyclohexane derivatives with different cyclic imide/amide termini, and their flexible, tetramethylene analogues were synthesized and pharmacologically evaluated for 5-HT1A receptors. In vitro binding experiments revealed that all the compounds were potent 5-HT1A receptor agents (K i =1.9–74nM). Some derivatives tested additionally showed also high affinity for α1-adrenergic receptors (K i =2.9–101nM) and for 5-HT7 receptors. Functional in vivo examination revealed that rigid ligands with o-OCH3 group in the aryl moiety and cyclic imide system in the opposite terminal behaved like postsynaptic 5-HT1A receptor antagonists. On the other hand, unsubstituted, m-Cl, or m-CF3 substituted derivatives as well as those with cyclic amide group in the terminal fragment exhibited agonistic or partial agonistic activity. Three out of four derivatives tested, that is, postsynaptic 5-HT1A antagonists 9 and 10, and partial agonist 16, showed anxiolytic-like activity in the conflict drinking (Vogel) test in rats. [Copyright &y& Elsevier]

Considering the allosteric regulation of mGlu receptors for potential therapeutic applications, we developed a group of 1,2,4-oxadiazole derivatives that displayed mGlu 4 receptor positive allosteric modulatory activity (EC 50 = 282-656 nM). Selectivity screening revealed that they were devoid of activity at mGlu 1 , mGlu 2 and mGlu 5 receptors, but modulated mGlu 7 and mGlu 8 receptors, thus were classified as group III-preferring mGlu receptor agents. None of the compounds was active towards hERG channels or in the mini-AMES test. The most potent in vitro mGlu 4 PAM derivative 52 (N-(3-chloro-4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)phenyl)picolinamide) was readily absorbed after i.p. administration (male Albino Swiss mice) and reached a maximum brain concentration of 949.76 ng/mL. Five modulators ( 34 , 37 , 52 , 60 and 62 ) demonstrated significant anxiolytic- and antipsychotic-like properties in the SIH and DOI-induced head twitch test, respectively. Promising data were obtained, especially for N-(4-(5-(2-chlorophenyl)-1,2,4-oxadiazol-3-yl)-3-methylphenyl)picolinamide ( 62 ), whose effects in the DOI-induced head twitch test were comparable to those of clozapine and better than those reported for the selective mGlu 4 PAM ADX88178.

Among different approaches to the search for novel-safer and less addictive-opioid analgesics, biased agonism has received the most attention in recent years. Some μ-opioid receptor agonists with G protein bias, including SR compounds, were proposed to induce diminished side effects. However, in many aspects, behavioral effects of those compounds, as well as the mechanisms underlying differences in their action, remain unexplored. Here, we aimed to evaluate the effects of SR-14968 and SR-17018, highly G protein-biased opioid agonists, on antinociception, motor activity and addiction-like behaviors in C57BL/6J mice. The obtained results showed that the compounds induce strong and dose-dependent antinociception. SR-14968 causes high, and SR-17018 much lower, locomotor activity. Both agonists develop reward-associated behavior and physical dependence. The compounds also cause antinociceptive tolerance, however, developing more slowly when compared to morphine. Interestingly, SR compounds, in particular SR-17018, slow down the development of antinociceptive tolerance to morphine and inhibit some symptoms of morphine withdrawal. Therefore, our results indicate that SR agonists possess rewarding and addictive properties, but can positively modulate some symptoms of morphine dependence. Next, we have compared behavioral effects of SR-compounds and PZM21 and searched for a relationship to the substantial differences in molecular interactions that these compounds form with the µ-opioid receptor.

In line with recent clinical trials demonstrating that ondansetron, a 5-HT 3 receptor (5-HT 3 R) antagonist, ameliorates cognitive deficits of schizophrenia and the known procognitive effects of 5-HT 6 receptor (5-HT 6 R) antagonists, we applied the hybridization strategy to design dual-acting 5-HT 3 /5-HT 6 R antagonists. We identified the first-in-class compound FPPQ , which behaves as a 5-HT 3 R antagonist and a neutral antagonist 5-HT 6 R 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-HT 6 R inverse agonist SB399885 nor neutral 5-HT 6 R antagonist CPPQ reversed (PCP)-induced hyperactivity. Thus, combination of 5-HT 3 R antagonism and 5-HT 6 R 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-HT 3 /5-HT 6 receptors and encourage further studies on dual-acting 5-HT 3 /5-HT 6 R antagonists for the treatment of psychiatric disorders.

The cytotoxic activity of several serotonin transporter (SERT) inhibitors and subtype of serotonin receptor 1A (5-HT 1A receptor) ligands have been examined in androgen-insensitive human PC-3 prostate and neuroblastoma SH-SY5Y cancer cells. Almost all of the studied compounds (except 5-HT 1A receptor agonist (2 R )-(+)-8-Hydroxy-2-(di- n -propylamino)tetralin hydrobromide (8-OH-DPAT)) exhibited absolute cytotoxic activity against the examined cancer cells. The compound 4-Fluoro- N -[2-[4-(7-methoxy-1-naphthalenyl)-1-piperazinyl]ethyl]benzamide hydrochloride (S14506) that showed highest activity against neuroblastoma tumors was the 5-HT 1A receptor agonist (although not alike other 5-HT 1A receptor agonists). On the other hand, the compound 6-nitro-2-(4-undecylpiperazin-1-yl)quinoline hydrochloride (AZ07) that had the highest activity against PC-3 prostate cancer cells was a compound exhibiting antagonistic activity against the 5-HT 1A receptor. Thus, compounds of oncotoxic properties S14506 and AZ07 should be evaluated further for their potential use in the prevention and treatment of cancer. Most of the 15 compounds tested exhibited either agonistic or antagonistic activity for both the cyclic adenosine monophosphate (cAMP) and extracellular signal-regulated kinase 1 and 2 (ERK1/2) pathways in human embryonic kidney 293 (HEK293) cells that overexpress the 5HT1AR gene. However, compounds paroxetine, N -Ac-paroxetine and 2-[4-(cyclobutylmethyl)piperazin-1-yl]-6-nitroquinoline hydrochloride (AB22) simultaneously exhibited antagonistic activity on the cAMP pathway and agonistic activity on the ERK1/2 pathway. Fluoxetine relative to compound AZ07 had almost three times lower cytotoxic activity against PC-3 prostate cancer cells. However, the proapoptotic activity of fluoxetine compared to compound AZ07 is almost two times higher which would suggest that the cytotoxic activity of both compounds may be dependent on different cell death mechanisms. Compound S14506 was found to be an antagonist of the serine-threonine protein kinase B (Akt) pathway. Prosurvival Akt activity may be reversed by Akt antagonists. Therefore, the antagonistic activity of S14506 on the Akt pathway may evoke caspase-3 expression and cytotoxicity. It appears that one should not expect a straightforward relationship between the activation of particular serotonergic pathways by selective serotonin reuptake inhibitors (SSRIs) and 5-HT 1A receptor ligands and their cytotoxic or cytoprotective activity. Additionally, nuclear transcription factor κB (NF-κB), which may be involved in 5-HT-dependent biochemical pathways by coordinating different subunits in the formation of a dimer, may regulate the transcription of different transduction pathways. Therefore, it can be suggested that the mechanism of the cytotoxic activity of certain compounds (serotonergic against nonserotonergic) may depend on the compound and cancer type being examined. Docking studies showed that S14506, buspirone and spiperone bind in similar ways in the 5-HT 1A receptor model and interacted with similar 5-HT 1A receptor residues. S14506 and spiperone were found to be located closer to both phenylalanines in TM6 than buspirone, thus exhibiting more antagonist binding modes.

Introduction: 5-HT 1A R was one of the first discovered serotonin receptors and is one of the most thoroughly studied. Dysfunctions associated with 5-HT 1A R neurotransmission are linked to several psychiatric disorders, including anxiety, depression, and movement disorders., Areas Covered: The current review covers patent literature published between January 2012 and May 2018. Queries were performed on Espacenet, SciFinder, clinicaltrials.gov, pharmacodia.com, and the websites of pharmaceutical companies., Expert Opinion: Several novel therapeutic applications have been proposed for 5-HT 1A R ligands, i.e. prostate cancer treatment, gastrointestinal and cardiopulmonary disorders, facilitation of urination and defecation, and L-DOPA-induced dyskinesia. Interestingly, no patent application has been filed by big pharma companies, while numerous researches are being conducted in smaller companies and academia.

A series of 5-aryl-1-alkylimidazole derivatives was synthesized using the van Leusen multicomponent reaction. The chemotype is the first example of low-basicity scaffolds exhibiting high affinity for 5-HT 7 receptor together with agonist function. The chosen lead compounds 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-1H-indole (AGH-107, 1o, K i 5-HT7  = 6 nM, EC 50  = 19 nM, 176-fold selectivity over 5-HT 1A R) and 1e (5-methoxy analogue, K i 5-HT7  = 30 nM, EC 50  = 60 nM) exhibited high selectivity over related CNS targets, high metabolic stability and low toxicity in HEK-293 and HepG2 cell cultures. A rapid absorption to the blood, high blood-brain barrier permeation and a very high peak concentration in the brain (C max  = 2723 ng/g) were found for 1o after i.p. (5 mg/kg) administration in mice. The compound was found active in novel object recognition test in mice, at 0.5, 1 and 5 mg/kg. Docking to 5-HT 7 R homology models indicated a plausible binding mode which explain the unusually high selectivity over the related CNS targets. Halogen bond formation between the most potent derivatives and the receptor is consistent with both the docking results and SAR. 5-Chlorine, bromine and iodine substitution resulted in a 13, 27 and 89-fold increase in binding affinities, respectively, and in enhanced 5-HT 1A R selectivity.

The newly synthesized analogs of NAN-190 containing m-Cl and m-CF(3) substituents in the arylpiperazine moiety and their conformationally restricted counterparts showed a very high 5-HT(1A )receptor affinity. In the LLR test, the flexible compounds 4a and 5a displayed features of a partial agonist and agonist, respectively. The conformational restriction in the tested structures caused alternations in the observed in vivo effects; compounds 4b and 5b were classified as an inactive agent and an antagonist of postsynaptic 5-HT(1A )receptors, respectively. Rigidification of MP3022 and its 5,6-dimethyl analog structures resulted in cis and trans stereoisomers 6b-9b with a 1- and 2-substituted benzotriazole moiety. In both series, in vitro experiments showed that the cis configurations of the compounds were better tolerated by 5-HT(1A) receptor sites than the trans ones. The conformational analysis revealed various spatial regions that can be explored by terminal benzotriazole fragments in those structures. Like the previously described cis-6b, the new ligand cis-7b, displayed features of a postsynaptic 5-HT(1A) receptor agonist, whereas cis-8b was characterized as a partial agonist of those receptor sites. It was suggested that the nonlinear geometry of the above agents has significant influence on the postsynaptic 5-HT(1A )receptor stimulation.

A series of 17 long-chain arylpiperazines containing bulky, complex imide systems (5,8-dimethyl-3b,9-epoxy-(3a,4,5,6,7,8,9,9a)-octahydro-1H-benzo[e]isoindole-1,3(2H)-dione or 4,9-diphenyl-4,9-epoxy-3a,4,9,9a-tetra-hydro-1H-benzo[f]isoindole-1,3(2H)-dione) was synthesized and evaluated for their affinity for serotonin 5-HT1A, 5-HT2A and dopamine D2 receptors. Most of the new compounds showed moderate activity at 5-HT1A binding sites (Ki = 100-492 nM), and two derivatives were found to have marked affinity for the 5-HT2A receptor subtype. None of the tested compounds displayed appreciable binding to dopamine D2 receptors Structure-activity relationships were discussed in respect to an arylpiperazine fragment, whereas the comparison of different imide terminals enabled determination of the size of a hydrophobic pocket (approximately 300 A3) within the 5-HT1A receptor.

Six extended analogues of the recently described peptides (LDVL, ADVL) were designed and synthesized on a solid support, and then impregnated on TLC stationary phases. The impact of the impregnated peptide sequence modifications on the chromatographic retard, Delta R(f) (difference in the migration of tested compound on control and impregnated plates), of 42 arylpiperazine 5-HT(1A) receptor ligands was studied. None of the new models tested made a better prediction of 5-HT(1A) affinity than that utilizing ADVL tetrapeptide. Further validation of the ADVL model on a set of 22 structurally differentiated 2-methoxy-phenylpiperazine derivatives confirmed its effectiveness in the affinity discrimination of a coherent group of 5-HT(1A) receptor ligands.

Two sets of new o-methoxyphenylpiperazine (MPP; series a) and 1,2,3,4-tetrahydroisoquinoline (THIQ; series b) derivatives, containing various imide moieties derived from NAN190, were synthesized and evaluated in vitro for their ability to bind to the serotonin 5-HT(1A) and 5-HT(2A) receptors. All new derivatives from series a demonstrated high 5-HT(1A) affinities, whereas THIQ analogues were much less active. With respect to 5-HT(2A) receptors, three MPP derivatives presented moderate activity but the rest of the investigated compounds were practically inactive. The influence of changes in terminus geometry on 5-HT(1A) receptor affinity was analyzed in regard to model compounds NAN190and MM199.

A series of 15 new 2-H- and 2-substituted 5-[omega-[4-(2-methoxyphenyl)-piperazinyl]-alkyl]-1,2,3,4-tetrahydro-gamma-carboline derivatives were prepared, and their affinity for 5-HT1A and 5-HT2A serotonin receptors was determined. Most of those hybrid compounds were found to bind with high affinity to 5-HT1A sites (Ki < 50 nM; 2d, 3a, 3b, 3d, 3e, 4b, 4d, 4e) and moreover two of them (4d, 4e) were mixed 5-HT1A/5-HT2A ligands. The results of a lower lip retraction test in rats indicated that the 2-acetyl derivative with a dimethylene spacer (2d) had features of a postsynaptic 5-HT1A receptor agonist, whereas its analogues with longer chains (3d and 4d) behaved like antagonists. Both 5-HT2A receptor ligands (4d, 4e) at high doses inhibited the (+/-)-DOI-induced head twitches in mice and were classified as weak antagonists of those receptors.

Structure-activity relationship studies of a series of novel 4, 6-disubstituted 2-(1-piperazinyl)pyridines were conducted to revise our model of serotonin 5-HT(2A) receptor antagonist. Target compounds were synthesized using the benzotriazole-assisted Katritzky method. The majority of those compounds were found to be selective 5-HT(2A)/5-HT(1A) receptor ligands, though less potent than their previously described pyrimidine counterparts. In particular, the three compounds 6-8 showed the highest 5-HT(2A) receptor affinity (K(i) = 34-78 nM) and were classified as 5-HT(2A) antagonists in in vivo experiments. The influence of the structural modifications on the in vitro results was discussed; however, the elucidation of the role of the central core system requires further studies.