Design and Synthesis of New Quinazolin-4-one Derivatives with Negative mGlu7 Receptor Modulation Activity and Antipsychotic-Like Properties.

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 reversed 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.

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

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

Tuning the activity of known drugs via the introduction of halogen atoms, a case study of SERT ligands - Fluoxetine and fluvoxamine.

The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. 'XSAR library analysis', a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.

Rationally designed N-phenylsulfonylindoles as a tool for the analysis of the non-basic 5-HT6R ligands binding mode.

Among all of the monoaminergic receptors, the 5-HT6R has the highest number of non-basic ligands (approximately 5% of compounds stored in 25th version of ChEMBL database have the strongest basic pKa below 5, calculated using the Instant JChem calculator plugin). These compounds, when devoid of a basic nitrogen, exhibit high affinity and remarkable selectivity. Despite a decade of research, no clues have been given for explanation of such an intriguing phenomenon. Here, a series of analogs of four known 5-HT6R ligands, has been rationally designed to approach this issue. For each of the synthesized 42 compounds, a binding affinity for 5-HT6R has been measured, together with a selectivity profile against 5-HT1AR, 5-HT2AR, 5-HT7R and D2R. Performed induced fit docking and molecular dynamics experiments revealed that no particular interaction was responsible for the activity of non-basic compounds. In fact, a plain N-phenylsulfonylindole (1e) was found to possess a moderate (5-HT6R, Ki = 159 nM) affinity. No other monoaminergic receptor has as simple and selective ligand as this one. Thus, it is stated that it binds to the receptor solely based on its conformation and as such, possesses a minimum amount of features, required for binding. Also, any functional group able to form an additional interaction with the receptor increase the binding affinity, like in the case of two highly active non-basic compounds 3e and 5g (5-HT6R, Ki = 65 nM and 38 nM, respectively).

Virtual screening-driven discovery of dual 5-HT6/5-HT2A receptor ligands with pro-cognitive properties.

A virtual screening campaign aimed at finding structurally new compounds active at 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, 5-HT6R Ki = 91 nM), was selected as a hit for further optimization. As expected, the chemical scaffold of selected compound was significantly different from all the serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, provided 43 compounds representing different substitution patterns. The derivative 42, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (5-HT6R Ki = 25, 5-HT2AR Ki = 32 nM), was selected as a lead and showed a good brain/plasma concentration profile, and it reversed phencyclidine-induced memory impairment. Considering the unique activity profile, the obtained series might be a good starting point for the development of a novel antipsychotic or antidepressant with pro-cognitive properties.

2-Aminoimidazole-based antagonists of the 5-HT6 receptor - A new concept in aminergic GPCR ligand design.

A new strategy in the design of aminergic GPCR ligands is proposed - the use of aromatic, heterocyclic basic moieties in place of the evergreen piperazine or alicyclic and aliphatic amines. This hypothesis has been tested using a benchmark series of 5-HT6R antagonists obtained by coupling variously substituted 2-aminoimidazole moieties to the well established 1-benzenesulfonyl-1H-indoles, which served as the ligands cores. The crystallographic studies revealed that upon protonation, the 2-aminoimidazole fragment triggers a resonance driven conformational change leading to a form of higher affinity. This molecular switch may be responsible for the observed differences in 5-HT6R activity of the studied chemotypes with different amine-like fragments. Considering the multiple functionalization sites of the embedded guanidine fragment, diverse libraries were constructed, and the relationships between the structure and activity, metabolic stability, and solubility were established. Compounds from the N-(1H-imidazol-2-yl)acylamide chemotype (10a-z) exhibited high affinity for 5-HT6R and very high selectivity over 5-HT1A, 5-HT2A, 5-HT7 and D2 receptors (negligible binding), which was attributed to their very weak basicity. The lead compound in the series 4-methyl-5-[1-(naphthalene-1-sulfonyl)-1H-indol-3-yl]-1H-imidazol-2-amine (9i) was shown to reverse the cognitive impairment caused by the administration of scopolamine in rats indicating procognitive potential.

Fluorinated indole-imidazole conjugates: Selective orally bioavailable 5-HT7 receptor low-basicity agonists, potential neuropathic painkillers.

The 5-HT7 receptor has recently gained much attention due to its involvement in multiple physiological functions and diseases. The insufficient quality of the available molecular probes prompted design of fluorinated 3-(1-alkyl-1H-imidazol-5-yl)-1H-indoles as a new generation of selective 5-HT7 receptor agonists. A potent and drug-like agonist, 3-(1-ethyl-1H-imidazol-5-yl)-5-iodo-4-fluoro-1H-indole (AGH-192, 35, Ki 5-HT7R = 4 nM), was identified by optimizing the halogen bond formation with Ser5.42 as the supposed partner. The compound was characterized by excellent water solubility, high selectivity over related CNS targets, high metabolic stability, oral bioavailability and low cytotoxicity. Rapid absorption into the blood, medium half-life and a high peak concentration in the brain Cmax = 1069 ng/g were found after i.p. (2.5 mg/kg) administration in mice. AGH-192 may thus serve as the long-sought tool compound in the study of 5-HT7 receptor function, as well as a potential analgesic, indicated by the antinociceptive effect observed in a mouse model of neuropathic pain.

Search for a 5-CT alternative. In vitro and in vivo evaluation of novel pharmacological tools: 3-(1-alkyl-1H-imidazol-5-yl)-1H-indole-5-carboxamides, low-basicity 5-HT7 receptor agonists.

Close structural analogues of 5-carboxamidotryptamine (5-CT) based on the newly discovered indole-imidazole scaffold were synthesized and evaluated to search for a 5-HT7 receptor agonist of higher selectivity. In vitro drug-likeness studies and in vivo pharmacological evaluation of potent and selective low-basicity 5-HT7 receptor agonists, previously published 7 (3-(1-ethyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide, AH-494) and 13 (3-(1-methyl-1H-imidazol-5-yl)-1H-indole-5-carboxamide), have supported their usefulness as pharmacological tools. Comprehensive in vitro comparison studies between 7, 13 and the commonly used 5-CT showed their very similar ADMET properties. Compound 7 at 1 mg kg-1 reversed MK-801-induced disruption in novel object recognition in mice and alleviated stress-induced hyperthermia (SIH) at high doses. Taking into account both in vitro and in vivo data, 7 and 13 may be considered as alternatives to 5-CT as pharmacological tools with important additional benefit associated with their low-basicity: high selectivity over 5-HT1AR.

5-HT1A receptor ligands and their therapeutic applications: review of new patents.

INTRODUCTION: 5-HT1AR was one of the first discovered serotonin receptors and is one of the most thoroughly studied. Dysfunctions associated with 5-HT1AR 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-HT1AR 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.

The effect of the intramolecular C-H⋯O interactions on the conformational preferences of bis-arylsulfones - 5-HT6 receptor antagonists and beyond.

The development of compounds with enhanced activity and selectivity by a conserved spatial orientation of the pharmacophore elements has a long history in medicinal chemistry. Rigidified compounds are an example of this concept. However, the intramolecular interactions were seldom used as a basis for conformational restraints. Here, we show the weak intramolecular interactions that contribute to the relatively well-conserved geometry of N1-arylsulfonyl indole derivatives. The structure analysis along with quantum mechanics calculations revealed a crucial impact of the sulfonyl group on the compound geometry. The weak intramolecular C-H⋯O interaction stabilizes the mutual "facing" orientation of two aromatic fragments. These findings extend the pharmacological interpretation of the sulfonyl group role from the double hydrogen bond acceptor to the conformational scaffold based on intramolecular forces. This feature has, to date, been omitted in in silico drug discovery. Our results should increase the awareness of researchers to consider the conformational preference when designing new compounds or improving computational methods.

Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol.

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-HT7 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, EC50 = 19 nM, 176-fold selectivity over 5-HT1AR) and 1e (5-methoxy analogue, K i 5-HT7 = 30 nM, EC50 = 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 (Cmax = 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-HT7R 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-HT1AR selectivity.