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Approximately 40% of Parkinson's disease (PD) patients that take mostly dopamine receptor agonists for motor fluctuations, experience the return of symptoms between regular doses. This is a phenomenon known as 'OFF periods.' Positive allosteric modulators (PAMs) of metabotropic glutamate receptor 4 (mGluR4) are a promising non-dopaminergic mechanism with potential to address the unmet need of patients suffering from OFF periods. Foliglurax is the first mGluR4 PAM that has advanced into clinical testing in PD patients.We summarize the chemistry, pharmacokinetics, and preclinical pharmacology of foliglurax. Translational PET imaging studies, clinical efficacy data, and a competitive landscape analysis of available therapies are presented to the readers. In this Perspective article, foliglurax is used as a case study to illustrate the inherent RD challenges that companies face when developing drugs. These challenges include the delivery of drugs acting through novel mechanisms, long-term scientific investment, and commercial success and shorter-term positive financial returns.Failure to meet the primary and secondary endpoints in a Phase 2 study led Lundbeck to discontinue the development of foliglurax. Understanding the evidence supporting compound progression into Phase 2 will enable the proper assessment of the therapeutic potential of mGluR4 PAMs.

Drug discovery research is a complex undertaking conducted by teams of scientists representing the different areas involved. In addition to a strong familiarity with existing knowledge, key relevant concepts remain unknown as activities start. This is often an accepted risk, mitigated by gaining understanding in real time as the project develops. Chemicals play a role in all biology studies conducted in the context of drug discovery, whether endogenously or exogenously added to the system under study. Furthermore, new knowledge often flourishes at the interface of existing areas of expertise. Due to differences in their training, adding a chemist's perspective to research teams would at least avoid potentially costly mistakes and ideally make any biology research richer. Thus, it would seem natural that one such team member be a chemist. Still, as that may not always be the case, we present some suggestions to minimize the risk of irreproducibility due to chemistry-related issues during biology research supporting drug discovery and make these efforts more robust and impactful. These include discussions on identity and purity, target and species selectivity, and chemical modalities such as orthosteric or allosteric small molecules or antibodies. Given the immense diversity of potential chemical/biological system interactions, we do not intend to provide a foolproof guide to conduct biological experimentation. Investigate at your own peril!

Medicinal chemists are accountable for embedding the appropriate drug target profile into the molecular architecture of a clinical candidate. An accurate characterization of the functional effects following binding of a drug to its biological target is a fundamental step in the discovery of new medicines, informing the translation of preclinical efficacy and safety observations into human trials. Membrane-bound proteins, particularly ion channels and G protein-coupled receptors (GPCRs), are biological targets prone to allosteric modulation. Investigations using allosteric drug candidates and chemical tools suggest that their functional effects may be tailored with a high degree of translational alignment, making them molecular tools to correct pathophysiological functional tone and enable personalized medicine when a causative target-to-disease link is known. We present select examples of functional molecular fine-tuning of allosterism and discuss consequences relevant to drug design.

Drug discovery research is a complex undertaking conducted by teams of scientists representing the different areas involved. In addition to a strong familiarity with existing knowledge, key relevant concepts remain unknown as activities start. This is often an accepted risk, mitigated by gaining understanding in real time as the project develops. Chemicals play a role in all biology studies conducted in the context of drug discovery, whether endogenously or exogenously added to the system under study. Furthermore, new knowledge often flourishes at the interface of existing areas of expertise. Due to differences in their training, adding a chemist’s perspective to research teams would at least avoid potentially costly mistakes and ideally make any biology research richer. Thus, it would seem natural that one such team member be a chemist. Still, as that may not always be the case, we present some suggestions to minimize the risk of irreproducibility due to chemistry-related issues during biology research supporting drug discovery and make these efforts more robust and impactful. These include discussions on identity and purity, target and species selectivity, and chemical modalities such as orthosteric or allosteric small molecules or antibodies. Given the immense diversity of potential chemical/biological system interactions, we do not intend to provide a foolproof guide to conduct biological experimentation. Investigate at your own peril!

Drug design necessitates a clear understanding of the phenotypic response to be elicited by a given ligandtarget interaction. This relationship is relatively well understood for classical biological targets of drug action, but for some novel targets, notably those amenable to allosteric modulation, developing such understanding may represent a more challenging task. In order to gain knowledge on the nature of the functional response derived from mGlu4 receptor activation, its molecular and cell biology are reviewed, including signalling pathways involved, receptor localization in central nervous system and beyond, and potential genetic links to disease. Broadly held views for both, orthosteric agonists as well as allosteric modulators, are compared with specific observations for the case of mGlu4 receptor activation via orthosteric and allosteric mechanisms. First, sub-type selectivity and brain penetration of amino acid mGlu4 receptor agonists are discussed, followed by the quantification of functional allosteric effects, the potential role of heterodimers in the functional response, and the observation of supra-physiological efficacy of mGlu4 receptor PAMs. We show that, in our analysis, these attributes differ from those that may be expected by extrapolating from broad knowledge. In addition, recent progress with mGlu4 receptor radioligands and PET ligands is summarized.

Harmaline induces tremor in animals resembling essential tremor which has been suggested to result from activation of the glutamatergic olivo-cerebellar projection. The aim of the present study was to examine the effects of systemic administration of Lu AF21934, a brain-penetrating positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu4), on the harmaline-induced tremor and other forms of motor activity in rats using fully automated Force Plate Actimeters. The influence of harmaline on the mGlu4 mRNA expression in the cerebellum and inferior olive was analysed by in situ hybridization. Harmaline at a dose of 15 mg/kg (ip) triggered tremor which was manifested by an increase in the power within 9–15 Hz band and in the tremor index (a difference in power between bands 9–15 Hz and 0–8 Hz). Harmaline induced a biphasic effect on mobility, initially inhibiting the exploratory locomotor activity of rats (0–30 min after administration), followed by an increase in their basic activity. Lu AF21934 (0.5–5 mg/kg sc) did not influence tremor but at doses of 0.5 and 2.5 mg/kg reversed harmaline-induced hyperactivity. MGlu4 mRNA expression was high in the cerebellar cortex and low in the inferior olive. Repeated harmaline (15 mg/kg ip once a day for 5 days] decreased mGlu4 mRNA in the cerebellum and inferior olive. The present study indicates that the mGlu4 stimulation counteracts hyperactivity induced by harmaline which suggests the involvement of cerebellar glutamatergic transmission in this process. In contrast, neuronal mechanisms involved in tremor seem to be insensitive to the stimulation of mGlu4.

Rationale Diverse preclinical studies suggest the potential therapeutic utility of the modulation of the glutamatergic system in brain via metabotropic glutamate (mGlu) receptors. Lu AF21934, a positive allosteric modulator of the mGlu4 receptor, was previously shown to reverse behavioral phenotypes in animal models thought to mimic positive, negative, and cognitive symptoms of schizophrenia. Objectives To begin elucidating the brain circuitry involved in mGlu4 receptor pharmacology and add mechanistic support to Lu AF21934-induced phenotypic responses, the potential involvement of 5-HT1A receptors in these antipsychotic-like effects was explored. The tests used were the following: MK-801-induced hyperactivity and 2,5-dimethoxy-4-iodoamphetamine (DOI)-induced head twitches in mice, for positive symptoms; MK-801-induced disruptions of social interactions for negative symptoms; and novel object recognition and spatial delayed alteration test for cognitive symptoms. The microdialysis studies in which the effect of Lu AF21934 on MK-801-induced dopamine and serotonin release was investigated. Results The effects caused by Lu AF2193 were inhibited by administration of the selective 5-HT1A receptor antagonist WAY100635 (0.1 mg/kg). That inhibition was observed across all models used. Moreover, the concomitant administration of sub-effective doses of Lu AF21934 and a sub-effective dose of the selective 5-HT1A receptor agonist tool compound (R)-(+)-8-hydroxy-DPAT hydrobromide (0.01 mg/kg) induced a clear antipsychotic-like effect in all the procedures used. Lu AF21934 (5 mg/kg) also inhibited MK-801-induced increase in dopamine and 5-HT release. Conclusions The actions of Lu AF21934 are 5-HT1A receptor-dependent. Activation of the mGlu4 receptor may be a promising mechanism for the development of novel antipsychotic drugs, efficacious toward positive, negative, and cognitive symptoms. Electronic supplementary material The online version of this article (doi:10.1007/s00213-014-3657-4) contains supplementary material, which is available to authorized users.

Background Male Wistar rats were used to verify the hypothesis that metabotropic glutamate 4 (mGlu 4 ) receptor ligands may modulate the locomotor effects evoked by cocaine or nicotine. Methods The preferential mGlu 4 receptor orthosteric agonist (2S)-2-amino-4-[hydroxy[hydroxy(4-hydroxy-3-methoxy-5-nitrophenyl)methyl]phosphoryl]butanoic acid (LSP1-2111) and the mGlu 4 receptor positive allosteric modulator (+)- cis - N 1 -(3,4-dichlorophenyl)cyclohexane-1,2-dicarboxamide (Lu AF21934) were used in the study. Rats were given repeated pairings of a test environment with cocaine (10 mg/kg), nicotine (0.4 mg/kg) or the respective vehicles for 5 days. On day 10, animals were challenged with cocaine (10 mg/kg, cocaine sensitization), nicotine (0.4 mg/kg, nicotine sensitization) or vehicle (conditioned hyperlocomotion) in experimental cages. Results Given on day 10, LSP1-2111 (3 mg/kg) as well as Lu AF21934 (2.5–5 mg/kg) decreased the expression of cocaine sensitization. In another set of experiments, LSP1-2111 (3 mg/kg) and Lu AF21934 (5 mg/kg) administered on day 10 attenuated the conditioned hyperlocomotion in rats treated repeatedly with cocaine. Neither LSP1-2111 (1–3 mg/kg) nor Lu AF21934 (2.5–5 mg/kg) changed the expression of nicotine sensitization and conditioned hyperlocomotion in rats treated repeatedly with nicotine. None of the mGlu 4 receptor agonist/modulator altered the basal locomotor activity or acute hyperactivity to cocaine or nicotine. Conclusions The present data indicate that pharmacological stimulation of mGlu 4 receptors reduces the cocaine-induced expression of sensitization as well as conditioned hyperactivity. In contrast, mGlu 4 receptor activation seems to be devoid of any effect on the locomotor effects of nicotine.

The NPY5 receptor binding and pharmacokinetic properties of a novel series of cis-1-oxo-heterocyclyl-4-amido-cyclohexane derivatives are described.

LSP1-2111 is a group III metabotropic glutamate receptor agonist with preference toward the mGlu4 receptor subtype. This compound has been extensively used as a tool to explore the pharmacology of mGlu4 receptor activation in preclinical animal behavioral models. However, the blood-brain barrier penetration of this amino acid derivative has never been studied. We report studies on the central nervous system (CNS) disposition of LSP1-2111 using quantitative microdialysis in rat. Significant unbound concentrations of the drug relative to its in vitro binding affinity and functional potency were established in extracellular fluid (ECF). These findings support the use of LSP1-2111 to study the CNS pharmacology of mGlu4 receptor activation through orthosteric agonist mechanisms.

Background and Purpose Because agonists at metabotropic glutamate receptors exert beneficial effects in schizophrenia, we have assessed the actions of Lu AF21934 and Lu AF32615, two chemically distinct, selective and brain-penetrant positive allosteric modulators (PAMs) of the mGlu4 receptor, in several tests reflecting positive, negative and cognitive symptoms of schizophrenia in rodents. Experimental Approach Hyperactivity induced by MK-801 or amphetamine and head twitches induced by 2,5-dimethoxy-4-iodoamphetamine (DOI) in mice were used as models for positive symptoms. Disruption of social interaction and spatial delayed alternation tests induced by MK-801 in rats were used as models for negative and cognitive symptoms of schizophrenia, respectively. Key Results Lu AF21934 (0.1–5 mg·kg−1) and Lu AF32615 (2–10 mg·kg−1) dose-dependently inhibited hyperactivity induced by MK-801 or amphetamine. They also antagonized head twitches and increased frequency of spontaneous excitatory postsynaptic currents (EPSCs) in brain slices, induced by DOI. In mice lacking the mGlu4 receptor (mGlu4−/−) mice, Lu AF21934 did not antagonize DOI-induced head twitches. MK-801-induced disruption in the social interaction test was decreased by Lu AF21934 at 0.5 mg·kg−1 and by Lu AF32615 at 10 mg·kg−1. In the delayed spatial alternation test, Lu AF21934 was active at 1 and 2 mg·kg−1, while Lu AF32615 was active at 10 mg·kg−1. Conclusions and Implications We propose that activation by PAMs of the mGlu4 receptor is a promising approach to the discovery of novel antipsychotic drugs.

Society expects that the wave of contemporary new discoveries in biological sciences will soon lead to novel treatments for human diseases, including many devastating brain disorders. Historically, medicinal chemists have contributed to drug discovery teams in ways that synergize with those from their partner sciences, and help transform new knowledge into the ultimate tangible asset: a new drug. The optimal balance of resources and the right strategy to minimize the risk of late clinical failure may differ for different therapeutic indications. Recent progress in the oncology and neuroscience therapeutic areas is compared and contrasted, in particular looking at the biological target space and functional attributes of recently FDA-approved drugs and those in the late clinical pipeline. Medicinal chemists are poised to have major influence in neuroscience drug research, and examples of areas of potential impact are presented, together with a discussion of the soft skills they bring to their project teams and why they have been so impactful.

The use of deuterium substitution in an effort to produce kinetic isotope effects (KIEs) that favorably alter pharmacokinetics and metabolism in drug discovery has accelerated in the last decade. While the effects of deuteration remain highly experimentally determined and are unpredictable, an increasing number of deuterated drug candidates have progressed from early patent filings to successful proof-of-concept human studies, including the first FDA-approved deuterated drug. The scope of use of KIEs in drug design has expanded, and now deuteration of drug candidates and tool compounds, including imaging ligands, has become a welcome instrument in the arsenal of medicinal chemists. It is expected that experimentation with strategic introduction of deuterium into the structures of organic compounds will continue to increase and may enable the future development of a variety of novel drugs and chemical tools. In this chapter an update on the topic of deuterium substitution in medicinal chemistry will be provided, focusing on the diversity of ways in which medicinal chemists are using deuteration in their efforts to deliver better drugs.

A novel series of trans-1,3-cyclohexyl diamides was discovered and characterized as mGluR5 negative allosteric modulators (NAMs) lacking an alkyne moiety. Conformational constraint of one of the amide bonds in the diamide template led to a spirooxazoline template. A representative compound (24d) showed good in vitro potency, high CNS penetration and, upon subcutaneous dosing, demonstrated efficacy in the mouse marble burying test, generally used as indicative of potential anxiolytic activity.

Research in life sciences is witnessing the emergence of new knowledge at a greater pace than ever before. This is starting to translate into innovative therapeutic treatments and approaches. The use of chemicals to modify the course of human disease has evolved into a number of modalities, which may arbitrarily be classified as biologics or small-molecule treatments. Some of the characteristics of these two are compared and contrasted. The term “allosteric modulators” is generally used to describe small molecules that change the attributes of large biological macromolecules, such as membrane-bound receptors, ion channels and transporters, as well as soluble enzymes. The rationale that stimulated the research into allosteric drugs in the mid-1990’s is presented, including perspectives on the early learnings that have emerged such as “flat structure–activity relationships” and “functional switches”, and how subtle differences in mechanisms of allosteric modulation can impact drug discovery.

Although the concept of allosterism has been known for over half a century, its application in drug discovery has exploded in recent years. The emergence of novel technologies that enable molecular-level ligand-receptor interactions to be studied in studied in unprecedented detail has driven this trend. This book, written by the leaders in this young research area, describes the latest developments in allosterism for drug discovery. Bringing together research in a diverse range of scientific disciplines, Allosterism in Drug Discovery is a key reference for academics and industrialists interested in understanding allosteric interactions. The book provides an in-depth review of research using small molecules as chemical probes and drug candidates that interact allosterically with proteins of relevance to life sciences and human disease. Knowledge of these interactions can then be applied in the discovery of the novel therapeutics of the future. This book will be useful for people working in all disciplines associated with drug discovery in academia or industry, as well as postgraduate students who may be working in the design of allosteric modulators.

4-(1-Phenyl-1H-pyrazol-4-yl)quinoline (1) was identified by screening the Lundbeck compound collection, and characterized as having mGlu4 receptor positive allosteric modulator properties. Compound 1 is selective over other mGlu receptors and a panel of GPCRs, ion channels and enzymes, but has suboptimal lipophilicity and high plasma and brain non-specific binding. In view of the challenges at the hit-to-lead stage previously reported in the development of mGlu4 receptor positive allosteric modulators (PAMs), a thorough structure-mGlu4 PAM activity relationship study was conducted to interrogate the chemical tractability of this chemotype. The central pyrazole ring tolerates the addition of one or two methyl groups. The C-7 position of the quinoline ring provides a site tolerant to hydrophilic substituents, enabling the design of diverse analogs with good in vitro mGlu4 PAM potency and efficacy, as well as improved microsomal turnover in vitro, compared to 1. In spite of the excellent ligand efficiency of 1 (LE = 0.43), optimization of in vitro potency for this series reached a plateau around EC50 = 200 nM.

Metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) have previously been implicated in a number of pathophysiological conditions, based on preclinical, and to some extent clinical, proof of concept for migraine, gastroesophageal reflux disease, Parkinson's disease and anxiety. In the past, the potential use of known mGlu5 antagonists for the treatment of lower urinary tract disorders was disclosed. In the patent evaluated herein, novel derivatives of 4-(prop-2-ynylidene)piperidine are described and claimed by Recordati Ireland Ltd, Ireland, as NAMs at mGlu5 for the treatment of lower urinary tract disorders. Selected compounds reported in this application were efficacious in the cystometry model of bladder dysfunction in conscious rats, and mGlu5 NAMs are, therefore, suggested to have potential for the treatment of lower urinary tract disorders.

The design, synthesis and structure-activity relationship studies of a novel series of CRF-1 receptor antagonists, the 2-arylpyrimidines, are described. The effects of substitution on the aromatic ring and the pyrimidine core on CRF-1 receptor binding were investigated. A number of compounds with K(i) values below 10 nM and lipophilicity in a minimally acceptable range for a CNS drug (cLogP5) were discovered.

The design, synthesis and structure-activity relationships of a novel series of CRF-1 receptor antagonist, the 1-aryl-4-alkylaminoisoquinolines, is described. The effects of substitution on the aromatic ring, the amino group and the isoquinoline core on CRF-1 receptor binding were investigated.

The synthesis and biological activity of a novel series of thrombin receptor antagonists is described. This series of compounds showed excellent in vitro and in vivo potency. The most potent compound 40 had an IC(50) of 7.6 nM and showed robust inhibition of platelet aggregation in a cynomolgus monkey model after oral administration.

In this review, we aim to present, discuss and clarify our current understanding regarding the prediction of possible antipsychotic effects of metabotropic glutamate (mGlu) receptor ligands. The number of preclinical trials clearly indicates, that this group of compounds constitutes an excellent alternative to presently used antipsychotic therapy, being effective not only to positive, but also negative and cognitive symptoms of schizophrenia. Although the results of clinical trials that were performed for the group of mGlu2/3 agonists were not so enthusiastic as in animal studies, they still showed that mGlu ligands do not induced variety of side effects typical for presently used antipsychotics, and were generally well tolerated. The lack of satisfactory effectiveness towards schizophrenia symptoms of mGlu2/3 activators in humans could be a result of variety of uncontrolled factors and unidentified biomarkers different for each schizophrenia patient, that should be taken into consideration in the future set of clinical trials. The subject is still open for further research, and the novel classes of mGlu5 or mGlu2/3 agonists/PAMs were recently introduced, including the large group of compounds from the third group of mGlu receptors, especially of mGlu4 subtype. Finally, more precise treatment based on simultaneous administration of minimal doses of the ligands for two or more receptors, seems to be promising in the context of symptoms-specific schizophrenia treatment.

In the last ~30 years, scientists have made great strides in understanding the biological function of group I metabotropic glutamate receptors (mGlu) in health and disease, as well as developing a broad array of potent and selective agents able to activate or inhibit these receptors. This article provides a comprehensive review of the most recent group I mGlu modulators published in patent and non-patent literatures from 2014 to May, 2015, including design, structure-activity relationship, in silico, in vitro and in vivo properties of key compounds. The current status of clinical mGlu5 negative allosteric modulators (NAMs) and the development of mGlu1 and mGlu5 PET ligands are also highlighted. While the therapeutic potential for group I mGlu modulating agents appears high, significant challenges remain. Strategies to reduce clinical development risks and mitigate important side effects, including psychotomimetic events observed with several mGlu5 NAMs and cellular toxicity associated with mGlu5 positive allosteric modulators (PAMs), while retaining therapeutic efficacy through approaches such as biased ligand signaling are discussed.

The structure–activity relationship (SAR) of the lactone ring of himbacine derived thrombin receptor (PAR-1) antagoinsts (e.g., 2 – 5 ) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of himbacine in basic conditions at elevated temperature.

A number of fluorinated 1-aryl-tetrahydrocyclopentapyrazoles were synthesized and their insecticidal activity was evaluated. Some of the fluorinated compounds had significant insecticidal properties.

A convenient synthetic route to novel 4-arylpyrazoles is described. The potential for insecticidal activity through GABA channel blockage by this series of compounds, as well as their selectivity for insect versus mammalian receptors, are explored through in vitro and in vivo assays.

The discovery, synthesis and structure–activity studies of a novel series of 2-arylpyrimidin-4-ones as CRF-1 receptor antagonists is described. These compounds are structurally simple and display appropriate physical properties for CNS agents

Protease activated receptor-1 (PAR-1), also known as thrombin receptor, is present in a variety of cell types such as platelets and endothelial cells. PAR-1 is proteolytically activated by thrombin by cleavage at its extracellular domain, unmasking a new amino terminus, which internally binds to the proximal receptor, eliciting cellular activation. Inhibition of the cellular activation by thrombin is a potentially promising therapeutic approach for the treatment of thrombotic and vascular proliferative disorders such as atherosclerosis and restenosis. Reported herein is the pharmacology of potent, low molecular weight thrombin receptor antagonists from pyrroloquinazoline, benzimidazole, and himbacine series. In the radioligand binding assay, these compounds inhibited PAR-1 in a competitive manner. They also inhibited thrombin and agonist peptide induced human platelet aggregation in a dose-dependent manner. Additionally, these compounds showed dose-dependent inhibition of agonist-induced cytosolic Ca(+2) transients and thymidine incorporation in human coronary artery smooth muscle cells (hCASMC). The most potent compound among these antagonists showed a Ki of 12 nM in the radioligand binding assay and an IC50 of 70 nM in the platelet aggregation inhibition assay.

Two methods are described for the regiospecific synthesis of 3,4-fused-cycloalkyl-1-arylpyrazoles; the key step is the reaction between aryl hydrazines and cyclic α-(dimethoxymethyl)ketones. The latter are obtained by BF3-promoted alkylation of ketones with trimethylorthoformate.

International audience; Metabotropic glutamate 4 (mGlu4) receptor is a promising target for the treatment of motor deficits in Parkinson's disease (PD). This is due in part to its localization at key basal ganglia (BG) synapses that become hyperactive in this pathology, particularly striatopallidal synapses. In this context, mGlu4 receptor activation using either orthosteric agonists or positive allosteric modulators (PAMs) improves motor symptoms in rodent PD models in certain conditions. However, literature data show that mGlu4 receptor PAMs have no effect at striatopallidal GABAergic synapses (unless combined with an orthosteric agonist) and on the firing activity of pallidal neurons, and fail to provide significant motor improvement in relevant PD models. This questions the mechanistic hypothesis that mGlu4 receptor PAMs should act at striatopallidal synapses to alleviate PD motor symptoms. To shed light on this issue, we performed brain slice electrophysiology experiments. We show that Lu AF21934, an mGlu4 PAM small-molecule probe-compound, was ineffective at striatopallidal synapses at all concentrations tested, while it significantly inhibited corticostriatal synaptic transmission. Similarly, Lu AF21934 did not affect electrophysiology readouts at striatopallidal synapses in the presence of haloperidol or in 6-hydroxydopamine-lesioned rats. Interestingly, co-application of Lu AF21934 with a glutamate transporter inhibitor revealed a significant inhibitory action at striatopallidal synapses. Possibly, this effect could rely on increased level/permanence of glutamate in the synaptic cleft. Such differential efficacy of mGlu4 receptor PAMs at corticostriatal vs. striatopallidal synapses raises several issues regarding the synaptic target(s) of these drugs in the BG, and challenges the mechanisms by which they alleviate motor deficits in experimental PD models.

An efficient, multigram-scale synthesis of dihydronaphthofuranone 1 using a novel aryl intramolecular Diels–Alder reaction of propargyl trans -cinnamate 8 is described. Catalytic reduction of 1 gave the cis -fused tetrahydronaphthofuranone derivative 2 .

A parallel synthesis of racemic himbacine analogs was carried out by N-alkylation of various commercially available cyclic amine derivatives with the alkylating agent 4 which bears the tricyclic unit of himbacine. Several of these analogs have potency comparable to that of himbacine, albeit lacking the desired selectivity. Structure-activity relationship studies support the existence of a hydrophobic pocket in the receptor where the piperidine ring of dihydrohimbacine binds.

Profound changes continue shaping scientific and business strategies in the pharmaceutical industry. Up until very recently, academic centers and corporations worked somewhat in isolation. However, over the last few years, two specific changes started to change this situation. On one hand, academic organizations became more engaged in operations previously conducted mainly in the industry, such as actual drug design and high-throughput drug screening. Capabilities were enhanced, both human and technical, and consolidation of available “know-how” led to the establishment of several academic centers capable of influencing and making key contributions to early drug discovery research. Simultaneously, the pharmaceutical industry recognized the need to enhance their sources of innovation and engage in hitherto mainly unexplored areas of research, such as neuroinflammation. In the process, previously insular organizations became more open to collaborating, exchanging information and building knowledge with external partners. Challenges remain to maximize the productivity of these interactions, and to benefit the collaborating partners, and ultimately society, by boosting the success of drug discovery. Developing a common language to communicate respective views is a key step towards enabling the partners to learn from each other and work together. In recent years our company has established a variety of successful collaborations with external partners. This chapter summarizes at a high level some of our current research processes, the learnings from our interactions with academic partners and our assessment of how to build strong academic-industry research partnerships.

The usefulness of the GoAggIII reaction protocol in the determination of potential products of CP-450 enzyme metabolism is explored on Sch 57726, a selective c-GMP phosphodiesterase inhibitor. A single major ketone is found as product. In contrast, the reaction with m-CPBA affords a product of oxidative ring cleavage.

The resolution of (±)-2-methylpiperidine using d - and l -tartaric acid followed by direct conversion of the intermediate tartrate salts to ( R ) and ( S )- N -Boc-2-methylpiperidine is described. Also described is an NMR protocol for assessing the optical purity of the intermediate tartrate salts as well as the free bases. The resolved enantiomers showed an ee of >98% based on NMR integration.

Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration. Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu 4 receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests. In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen. The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT 1A receptors by WAY100635, or 5-HT 2A/2C receptors by ritanserin. These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents. Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages. This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.

Pyrazole 2a is a novel, potent ligand for insect GABA receptors obtained from housefly head membrane preparations (K(i)=8 nM). It is 500-fold selective against the mammalian receptor (mouse brain preparations). Its specifically tritiated version (2b) was synthesized by reduction of disulfide 10 with NaBH(4) followed by alkylation with [3H(3)]-CH(3)I.

Terms such as “nondruggable GPCRs” describe a unique group of GPCRs having strong biological hypothesis validation, but for which medicinal chemistry efforts based on orthosteric ligands have failed to produce marketed drugs (or even clinical development candidates). These receptors remain attractive as biological targets for new drugs, but a novel medicinal chemistry strategy must be developed to modulate their biological effects. This may be possible by modulating receptors using allosteric ligands, which interact with the receptor at a binding site topographically distinct from the endogenous ligand This account reviews emerging empirical observations on GPCR allosteric ligand design and presents a number of medicinal chemistry strategies to address current challenges in a productive manner from the drug discovery standpoint.

A mechanistic investigation into the recently reported intramolecular aryl Diels–Alder reaction was carried out using deuterium labeling. These studies led to the conclusion that the initial Diels–Alder adduct is isomerized to a highly conjugated tetra-ene intermediate which undergoes a stereospecific suprafacial 1,5-dienyl hydrogen shift to give the observed product.

Group III metabotropic glutamate (mGlu) receptors are localized in presynaptic terminals within basal ganglia (BG) circuitry that become hyperactive due to dopamine depletion in Parkinson's disease (PD). For this reason, group III mGlu receptors, in particular mGlu4, have been considered as key strategic targets for non-dopaminergic pharmacological treatments aimed at modulating these synapses, without producing the well known side-effects of l -DOPA, in particular the highly disabling l -DOPA-induced dyskinesia (LID). Herein we add physiological and functional support to this hypothesis using Lu AF21934, a novel selective and brain-penetrant mGlu4 receptor positive allosteric modulator (PAM) tool compound. By in vitro electrophysiological recordings we demonstrate that Lu AF21934 inhibits corticostriatal synaptic transmission and enhances the effect of the orthosteric mGlu4 receptor-preferred agonist LSP1-2111. In naive rats, Lu AF21934 dose-dependently (10 and 30 mg/kg) alleviated haloperidol-induced catalepsy. In hemiparkinsonian rats (unilateral 6-hydroxydopamine lesion of the substantia nigra pars compacta), Lu AF21934 alone did not affect akinesia at the doses tested (10 and 30 mg/kg). However, when Lu AF21934 was combined with sub-threshold doses of l -DOPA (1 and 5 mg/kg), it acted synergistically in alleviating akinesia in a dose-dependent manner and, notably, also reduced the incidence of LID but not its severity. Interestingly, these effects occurred at Lu AF21934 brain free concentrations that showed functional activity in in vitro screens (calcium flux and electrophysiology assays). These results support the potential for antiparkinsonian clinical use of a combined treatment consisting in l -DOPA and a mGlu4 receptor PAM to reduce efficacious l -DOPA doses (generally known as l -DOPA sparing), while maintaining the same benefit on PD motor troubles, and at the same time minimizing the development of LID. This article is part of a Special Issue entitled ‘Metabotropic Glutamate Receptors’.

Previous studies demonstrated that the Group III mGlu receptor-selective orthosteric agonist, LSP1-2111 produced anxiolytic- but not antidepressant-like effects upon peripheral administration. Herein, we report the pharmacological actions of Lu AF21934, a novel, selective, and brain-penetrant positive allosteric modulator (PAM) of the mGlu(4) receptor in the stress-induced hyperthermia (SIH), four-plate, marble-burying and Vogel's conflict tests. In all models, except Vogel's conflict test, a dose-dependent anxiolytic-like effect was seen. The anti-hyperthermic effect of Lu AF21934 (5 mg/kg) in the SIH test was inhibited by the benzodiazepine receptor antagonist flumazenil (10 mg/kg) and was not serotonin-dependent, as it persisted in serotonin-deficient mice and upon blockade of either 5-HT(1A) receptors by WAY100635, or 5-HT(2A/2C) receptors by ritanserin. These results suggest that the GABAergic system, but not the serotonergic system, is involved in the mechanism of the anxiolytic-like phenotype of Lu AF21934 in rodents. Lu AF21934 did not produce antidepressant-like effects in the tail suspension test (TST) in mice; however, it decreased the basal locomotor activity of mice that were not habituated to activity cages. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.

There is an increasing amount of evidence to support that activation of the metabotropic glutamate receptor 4 (mGlu4 receptor), either with an orthosteric agonist or a positive allosteric modulator (PAM), provides impactful interventions in diseases such as Parkinson’s disease, anxiety, and pain. mGlu4 PAMs may have several advantages over mGlu4 agonists for a number of reasons. As part of our efforts in identifying therapeutics for central nervous system (CNS) diseases such as Parkinson’s disease, we have been focusing on metabotropic glutamate receptors. Herein we report our studies with a series of tricyclic thiazolopyrazoles as mGlu4 PAMs.

The design, synthesis, and structure-activity relationships of a novel series of pyrazines, acting as corticotropin releasing factor-1 (CRF-1) receptor antagonists, are described. Synthetic methodologies were developed to prepare a number of substituted pyrazine cores utilizing regioselective halogenation and chemoselective derivatization. Noteworthy, an efficient 5-step synthesis was developed for the lead compound 59 (NGD 98-2), which required no chromatography. Compound 59 was characterized as an orally bioavailable, brain penetrant, and highly selective CRF-1 receptor antagonist. Occupancy of rat brain CRF-1 receptors was quantified using ex vivo receptor occupancy assays, using both brain tissue homogenates as well as brain slices receptor autoradiography. Behaviorally, oral administration of 59 significantly antagonized CRF-induced locomotor activity at doses as low as 10 mg/kg and dose-dependently reduced the restraint stress-induced ACTH increases.