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Abstract Allosteric modulators of G-protein-coupled receptors have lately gained significant traction in drug discovery. Recent studies have shown that allosteric modulation of serotonin 2C receptor (5-HT 2C) as a viable strategy for the treatment of various central nervous system (CNS) disorders. Considering the critical role of 5-HT 2C in the modulation of appetite, a selective positive allosteric modulator (PAM) of 5-HT 2C offers a new opportunity for anti-obesity therapeutic development. In this study, phenyl cyclopropyl-linked N -heterocycles were synthesized and evaluated at 5-HT 2C for agonist and PAM activity. Our study shows that imidazole linked phenyl cyclopropyl methanones has PAM activity on both 5-HT 2C and serotonin 2B receptor (5-HT 2B). Interestingly, piperazine linked phenyl cyclopropyl methanones (58) was active as PAM of 5-HT 2C (increased the E max of 5-HT to 139%), and as negative allosteric modulator (NAM) of 5-HT 2B (decreases EC 50 of 5-HT 10 times without affecting E max). Similar effect of compound 58 was observed with synthetic orthosteric agonist lorcaserin on 5-HT 2B. Molecular docking study revealed that all active compounds were binding to the predicted allosteric site on 5-HT 2C and shared a common interacting residues. Finally, compound 58 suppressed food intake in Sprague Dawley (SD) rats similar to lorcaserin after i.c.v. administration. Therefore, these results suggest that piperazine moiety is essential for dual activity (PAM & NAM) of compounds 58, and supports the hypothesis of 5-HT 2C PAM for the treatment of obesity similar to the full agonist. Graphical abstract Image 1 Highlights • A series of N -heterocycle linked phenyl cyclopropyl methanones were synthesized. • Three molecules were found active as allosteric modulators on serotonin receptors. • Compound 58 at 1 μM selectively exhibited PAM on 5-HT 2C and NAM on 5-HT 2B. • Compound 58 decreased food intake similar to full agonist lorcaserin in SD rats. [ABSTRACT FROM AUTHOR]

Abstract The N -methyl- D -aspartate receptor (NMDAR), a ligand-gated ion channel activated by L-glutamate and glycine, plays a major role in the synaptic plasticity underlying learning and memory. NMDARs are involved in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and NMDAR hypofunction is implicated in schizophrenia. Herein we describe structure-activity relationship (SAR) studies on 2-naphthoic acid derivatives to investigate structural requirements for positive and negative allosteric modulation of NMDARs. These studies identified compounds such as UBP684 (14b), which act as pan potentiators by enhancing NMDAR currents in diheteromeric NMDAR tetramers containing GluN1 and GluN2A-D subunits. 14b and derivatives thereof are useful tools to study synaptic function and have potential as leads for the development of drugs to treat schizophrenia and disorders that lead to a loss of cognitive function. In addition, SAR studies have identified a series of styryl substituted compounds with partial NAM activity and a preference for inhibition of GluN2D versus the other GluN2 subunits. In particular, the 3-and 2-nitrostyryl derivatives UBP783 (79i) and UBP792 (79h) had IC 50 s of 1.4 μM and 2.9 μM, respectively, for inhibition of GluN2D but showed only 70–80% maximal inhibition. GluN2D has been shown to play a role in excessive pain transmission due to nerve injury and potentially in neurodegenerative disorders. Partial GluN2D inhibitors may be leads for the development of drugs to treat these disorders without the adverse effects observed with full NMDAR antagonists. Graphical abstract Image 1 Highlights • SAR studies on 2-naphthoic acid derivatives revealed a series of NMDAR PAMs and NAMs. • 6-Alkyl substituted 2-naphthoic acid derivatives such as 14b are NMDAR PAMs. • Adding heteroatoms into the 6-alkyl chain generally led to NMDAR NAMs. • 7-(Nitrostyryl)-3-hydroxy-2-naphthoic acids (79h-j) are GluN2D preferring partial NMDAR NAMs. • NMDAR NAMs and PAMs may treat chronic pain and cognitive disorders, respectively. [ABSTRACT FROM AUTHOR]

Targeting CCR2 and CCR5 receptors is considered as promising concept for the development of novel antiinflammatory drugs. Herein, we present the development of the first probe-dependent positive allosteric modulator (PAM) of CCR5 receptors with a 2-benzazepine scaffold. Compound 14 (2-isobutyl- N -({[ N -methyl- N -(tetrahydro-2 H -pyran-4-yl)amino]methyl}phenyl)-1-oxo-2,3-dihydro-1 H -2-benzazepine-4-carboxamide) activates the CCR5 receptor in a CCL4-dependent manner, but does not compete with [ 3 H]TAK-779 binding at the CCR5. Furthermore, introduction of a p -tolyl moiety at 7-position of the 2-benzazepine scaffold turns the CCR5 PAM 14 into the selective CCR2 receptor antagonist 26b . The structure affinity and activity relationships presented here offer new insights into ligand recognition by CCR2 and CCR5 receptors. [ABSTRACT FROM AUTHOR]

Positive allosteric modulators of the AMPA receptors (AMPAR PAMs) have been proposed as new drugs for the management of various neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, attention deficit hyperactivity disorder, depression, and schizophrenia. The present study explored new AMPAR PAMs belonging to 3,4-dihydro-2 H -1,2,4-benzothiadiazine 1,1-dioxides (BTDs) characterized by the presence of a short alkyl substituent at the 2-position of the heterocycle and by the presence or absence of a methyl group at the 3-position. The introduction of a monofluoromethyl or a difluoromethyl side chain at the 2-position instead of the methyl group was examined. 7-Chloro-4-cyclopropyl-2-fluoromethyl-3,4-dihydro-4 H -1,2,4-benzothiadiazine 1,1-dioxide (15e) emerged as the most promising compound associating high in vitro potency on AMPA receptors, a favorable safety profile in vivo and a marked efficacy as a cognitive enhancer after oral administration in mice. Stability studies in aqueous medium suggested that 15e could be considered, at least in part, as a precursor of the corresponding 2-hydroxymethyl-substituted analogue and the known AMPAR modulator 7-chloro-4-cyclopropyl-3,4-dihydro-4 H -1,2,4-benzothiadiazine 1,1-dioxide (3) devoid of an alkyl group at the 2-position. [Display omitted] • This study explored new AMPAR PAMs belonging to 1,2,4-benzothiadiazine 1,1-dioxides. • The introduction of a mono/difluoromethyl side chain at the 2-position was examined. • Compound 15e associated high in vitro / in vivo potency and a favorable safety profile. • Stability studies suggested that 15e was in part a precursor of the AMPAR modulator 3. [ABSTRACT FROM AUTHOR]

The family of GABA-A receptors contains nineteen mammalian subunits from which pentameric, GABA gated anion channels are assembled. The subunit encoded by the GABRA6 gene is highly expressed in the cerebellum and the receptors to which it contributes have recently been demonstrated to be a promising candidate as a novel drug target. Here we examined a series of loreclezole derivatives for potentially selective action at α6β3γ2 receptors with the help of computational methods and functional testing with the two-electrode voltage clamp technique. The synthetic routes to some previously published ligands were improved, and a new derivative was synthesized based on computational docking results. This new loreclezole derivative, [ 3-(2-chloro-4-methylphenyl)-3-methylbutanenitrile ( 40 )] , was shown to display stronger modulatory action in concatenated α6β3γ2 receptors compared to their α1β3γ2 counterpart. The hypothetical bound state structure provides valuable guidance for future design of selective therapeutics. [Display omitted] • Loreclezole derivatives are synthetically versatile GABAA receptor modulators that tolerate a wide range of modifications. • Some derivatives displayed alpha6 over alpha1 preference. • Bound state structure prediction inspired the design of a compound with improved alpha6 preference. • Geminal demethylation of ketones for preparing quaternary centers. • Alcohol deoxygenation en route to alkanes. [ABSTRACT FROM AUTHOR]

The Secretin/Secretin receptor (SCTR) axis is well-known for its important role in water/salt homeostasis and blood pressure control. Recent studies revealed that absence of Secretin could lead to hypertension in animals and the administration of external Secretin leads to a sharp drop in blood pressure. Therefore, Secretin receptor has emerged as a crucial drug target of interest. In this report, using structure based drug design strategy, we have identified a small compound-based Secretin receptor modulator (i.e. purmorphamine or KSD179019). The virtual docking of KSD179019 with SCTR crystal structure and homology models revealed similar binding interactions. Based on active pharmacophores of KSD179019, several derivatives were designed and sythesized. SAR studies revealed that KSD179019 is the most effective SCTR modulator and chosen for further biological evaluation, including drug like properties and anti-hypertensive effect. KSD179019 not only has a similar blood pressure lowering effect as SCT peptide, but more importantly, it has a much longer half-life (∼8 h) and can be taken orally. Preliminary preclinical studies revealed extended bioavailability and low toxicity of this compound. [Display omitted] • Discovered a small molecule compound Purmorphamine as a modulator for Secretin receptor (SCTR). • SAR studies revealed the presence of morpholine core to be important for positive allosteric modulation of SCT function. • For the first time, we provide critical evidence for Purmorphamine to be used as novel anti-hypertensive drug candidate. • Preclinical studies revealed extended bioavailability and low toxicity of Purmorphamine. [ABSTRACT FROM AUTHOR]

The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized. A promising, pyrazole-containing new chemotype with good physicochemical and in vitro parameters was identified. Retrospective analysis based on homology modeling was also carried out. Besides its favorable in vitro characteristics, the most advanced derivative 69 also showed in vivo efficacy in a rodent model of cognition (scopolamine-induced amnesia in the mouse place recognition test) and acceptable pharmacokinetic properties. Based on the in vivo data, the resulting molecule with advanced drug-like characteristics has the possibility to improve cognitive performance in a biologically relevant dose range, further strengthening the view of the supportive role of α7 nACh receptors in the cognitive processes. Image 1 • Assessment the importance of the pharmacophoric elements of A-867744. • New heteroaromatic central cores were identified and characterized. • Pyrazole-containing chemotype showed good physicochemical and in vitro parameters. • The best compound showed in vivo efficacy in a rodent model of cognition. [ABSTRACT FROM AUTHOR]

We previously reported the 2-oxopyridine-3-carboxamide derivative EC21a as the first small synthetic CB2R positive allosteric modulator which displayed antinociceptive activity in vivo in an experimental mouse model of neuropathic pain. Herein, we extended the structure-activity relationships of EC21a through structural modifications regarding the p -fluoro benzyl moiety at position 1 and the amide group in position 3 of the central core. The characterization in vitro was assessed through radioligand binding experiments and functional assays (GTPγS, cAMP, βarrestin2). Among the new compounds, the derivatives A1 (SV-10a) and A5 (SB-13a) characterized respectively by fluorine atom or by chlorine atom in ortho position of the benzylic group at position 1 and by a cycloheptane-carboxamide at position 3 of the central core, showed positive allosteric behavior on CB2R. They enhanced the efficacy of CP55,940 in 35S]GTPγS assay, and modulated CP55,940-dependent βarrestin2 recruitment and cAMP inhibition. The obtained results extend our knowledge of the structural requirements for interaction with the allosteric site of CB2R. Image 1 • We synthesized 3-substituted 1,2-dihydropyridine-2-oxo derivatives. • Derivatives A1 and A5 were shown to be CB2R PAMs. • Their behaviour as PAMs was assessed through radioligand binding and functional assays. • A1 and A5 enhanced the efficacy of CP55,940 in 35S]GTPγS assay. • A1 and A5 modulated CP55,940-dependent βarrestin2 recruitment and cAMP inhibition. [ABSTRACT FROM AUTHOR]

The pentameric γ-aminobutyric acid type A receptors (GABA A Rs) are the major inhibitory ligand-gated ion channels in the central nervous system. They mediate diverse physiological functions, mutations in them are associated with mental disorders and they are the target of many drugs such as general anesthetics, anxiolytics and anti–convulsants. The five subunits of synaptic GABA A Rs are arranged around a central pore in the order β-α-β-α-γ. In the outer third of the transmembrane domain (TMD) drugs may bind to five homologous intersubunit binding sites. Etomidate binds between the pair of β – α subunit interfaces (designated as β+/α–) and R–mTFD-MPAB binds to an α+/β– and an γ+/β– subunit interface (a β– selective ligand). Ligands that bind selectively to other homologous sites have not been characterized. We have synthesized a novel photolabel, (2,6-diisopropyl-4-(3-(trifluoromethyl)-3H-diazirin-3-yl)phenyl)methanol or pTFD-di-iPr-BnOH). It is a potent general anesthetic that positively modulates agonist and benzodiazepine binding. It enhances GABA–induced currents, shifting the GABA concentration-response curve to lower concentrations. Photolabeling–protection studies show that it has negligible affinity for the etomidate sites and high affinity for only one of the two R–mTFD-MPAB sites. Exploratory site–directed mutagenesis studies confirm the latter conclusions and hint that pTFD-di-iPr-BnOH may bind between the α+/β– and α+/γ– subunits in the TMD, making it an α+ ligand. The latter α+/γ– site has not previously been implicated in ligand binding. Thus, pTFD-di-iPr-BnOH is a promising new photolabel that may open up a new pharmacology for synaptic GABA A Rs. Image 1 • PTFD-di-iPr-BnOH is a potent general anesthetic and enhances GABA's actions. • It photo-incorporates into intersubunit sites in the GABA(A)R's transmembrane domain. • Photo-protection shows it binds at either the γ+/β– or the α+/β– subunit interface. • Similarly, it does not bind in the β+/α– subunit interfaces (etomidate sites). • Site–directed mutagenesis suggests the α+/γ– interface is another site. [ABSTRACT FROM AUTHOR]

A scaffold hopping strategy converted the known 1-[(1-methyl-1H-imidazol-2-yl)methyl]-4-phenylpiperidine core (1 and 2) by cyclization to a fused [6 + 5+6] membered heterocyclic mGluR2 PAM scaffold. Pharmacophore guided structure−activity relationship (SAR) studies resulted in a series of potent and metabolically stable mGluR2 PAMs. A representative optimized compound (95) having the most balanced profile, demonstrated efficacy in the PCP-induced hyper-locomotion model in mice that revealed the new chemotype being a promising PAM lead targeting mGluR2 receptors and providing support for further translational studies. Image 1 • A novel series of dihydropyrazino-benzimidazoles in search of mGluR2 PAMs were discovered as potential antipsychotics. • Pharmacophore guided structure−activity relationship studies resulted in potent and metabolically stable mGluR2 PAMs. • Compound 95 showed the most balanced profile. • Compound 95 demonstrated efficacy in the PCP-induced hyperlocomotion model in mice. [ABSTRACT FROM AUTHOR]