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. 2010 Aug 13;1(8):433–438. doi: 10.1021/ml100181a

Discovery of N-Aryl Piperazines as Selective mGluR5 Potentiators with Improved In Vivo Utility

Ya Zhou †,§, Jason T Manka †,§, Alice L Rodriguez †,§, C David Weaver †,§,⊥, Emily L Days §,⊥, Paige N Vinson †,§, Satyawan Jadhav †,§, Elizabeth J Hermann †,§, Carrie K Jones †,§,∥, P Jeffrey Conn †,§, Craig W Lindsley †,‡,§, Shaun R Stauffer †,§,*
PMCID: PMC3539763  NIHMSID: NIHMS228903  PMID: 23308336

Abstract

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This letter describes the discovery, structure−activity relationship, and in vitro and in vivo pharmacological profile of a novel non-MPEP-derived mGluR5 positive allosteric modulator (PAM) based upon an N-aryl piperazine chemotype. This mGluR5 chemotype exhibits the ability to act as either a noncompetitive antagonist/negative allosteric modulator or a potentiator of the glutamate response, depending on the identity of the amide substituent, that is, a “molecular switch”. A rapidly optimized PAM, 10e (VU0364289), was shown to be potent and specific for the rat mGluR5 receptor and subsequently demonstrated to be efficacious in a clinically relevant rodent model predictive of antipsychotic activity, thus providing the first example of a centrally active mGluR5 PAM optimized from an HTS-derived mGluR5 noncompetitive antagonist.

Keywords: mGluR, potentiator, positive allosteric modulator, schizophrenia, hyperlocomotion

Schizophrenia affects 1% of the worldwide population with an onset most often during late adolescence. Currently available treatments, which include so-called “typical” and “atypical” antipsychotic drugs, fail to address all of the major symptom clusters of schizophrenia.1,2 Moreover, because of diminished cognitive and physical activity associated with these treatments, patient compliance is extremely poor.3 Thus, given the limitations of current therapies, there is a major medical need to discover novel approaches that could address all of the major symptom clusters (positive, negative, and cognitive) of schizophrenia with improved patient compliance and quality of life.

Positive allosteric modulators (PAMs) of the group I metabotropic glutamate receptor mGluR5 have emerged as a potentially novel approach to treat all major symptom domains of schizophrenia.1,4−7 Until recently, functionally efficacious and potent mGluR5 PAMs have been somewhat structurally limited in scope and slow to emerge. The reported prototypical mGluR5 PAMs (Figure 1) are represented by DFB (1),8 CPPHA (2),9,10 CDPPB (3),11,12 and ADX47273 (4);13−15 more recently, a series of MPEP-based pyrimidine (5a)16 and nicotinamide PAMs (5b) have been disclosed.17,18 Radioligand binding studies using mGluR5 negative allosteric modulator (NAM)-labeled MPEP analogues, such as [3H]3-methoxy-PEPy, have shown that DFB, CDPPB, ADX47273, and the recent MPEP-based PAMs (5b)18 bind and interact with a common allosteric binding site. The allosteric binding site for CPPHA appears to be a distinct site yet to be elucidated.9 Although the breadth of in vitro mGluR5 PAM chemotypes continues to grow, the identification of good in vivo tools for the field remains severely limited. CDPPB (2)9,10 and ADX47273 (4)13−15 are the only centrally active mGluR5 PAMs shown to be efficacious in two preclinical behavioral models that are sensitive to known antipsychotics. Unfortunately, because of their limited solubility and efficacy and in the case of CDPPB, the need for toxic vehicle formulations, the extent of in vivo pharmacological evaluation of these current tool compounds in higher models of cognition, including attention, working, and long-term memory function as well as transgenic models of schizophrenia, has not emerged.

Figure 1.

Figure 1

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Reported mGluR5 PAM chemotypes.

Ongoing evaluation of novel PAMs of mGluR5 in more native cellular contexts continues to shed light on the complexities of differential signaling and their potential impact in decision making for preclinical development candidate selection. Thus far, ligand-dependent differential activation of downstream signaling pathways by mGluR5 has been demonstrated by DFB and CPPHA.19 Even more concerning has been the identification of subtle “molecular switches” on allosteric mGluR5 ligands, which fundamentally alter the mode of pharmacology. This “molecular switch” to modulate pharmacological activity was first noted in the DFB series, wherein alternative substituents for the 3-F moiety resulted in an equipotent NAM (3-OMe) and a neutral ligand (3-Cl).8 Further examples were found in the MPEP-based pyrimidine scaffold 5a,16 wherein the regiochemistry of a single methyl group or introduction of a regioisomeric pyrimidine core could modulate pharmacology from PAM to NAM. Finally, we observed this in the ADX47273 scaffold as well.15 These findings in conjunction with the shortage of useful in vivo tools underscore the need for additional unique and overlapping chemotypes to aid in characterizing the breadth of anticipated pharmacological profiles of mGluR5 PAMs.

To this end, we recently reported on a series of structurally unique mGluR5 allosteric modulators containing a 2-pyridylpiperazine motif as noncompetitive mGluR5 antagonists/NAMs.20 The lead 2-pyridylpiperazine 6 (Figure 2) from this series was discovered from a functional HTS of 160000 compounds and was considered to be a significant departure from MPEP-based structures found within the mGluR5 noncompetitive antagonist field. Optimization of the N-aryl substituent identified a 2-thiazolyl replacement 7 as an improvement in potency. Further attempts to improve the NAM potency for the series through modification of the adamantyl amide moiety through an amide library scan were relatively unsuccessful; however, during the course of these studies, a weakly active PAM 8 was discovered (EC50 of 5.4 μM and an 86% response of the glutamate maximum) employing a 2-(benzyloxy)acetate amide moiety as a “molecular switch”. On the basis of its structural novelty versus known mGluR5 PAMs and physiochemical properties (MW < 300, cLog P = 2.4), we became interested in further optimization of 8. In this letter, we describe the structure−activity relationship (SAR), mGluR selectivity profile, preliminary radioligand binding data, in vitro DMPK profile, and in vivo behavioral data using a clinically relevant animal model predictive of antipyschotic activity.11,12,20

Figure 2.

Figure 2

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Generation of piperazine-based PAM 8 from NAM 6.

Efforts to optimize lead structure 8 as a PAM for mGluR5 focused on retaining the benzyloxyacetate amide unit that engendered the observed potentiation and explored the SAR of the western N-aryl substituent.21 The preparation of N-aryl analogues was conducted using either a SNAr reaction with an appropriate activated aryl fluoride or bromide using microwave-assisted organic synthesis or by performing a Pd-catalyzed amination reaction to give final compounds 10a−k (Scheme 1 and Table 1) in good yields. Alternatively, select N-aryl piperazines from commercial sources were prepared directly via amide coupling.22

Scheme 1.

Scheme 1

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Reagents: (a) Het-F/Ar-F, DMF, 6 h, 160 °C, 22−95%. (b) 2-(Benzyloxy)acetyl chloride, DMAP, DIPEA, DMF, room temperature, 60−95%. (c) Ar-Br, 5 mol % Pd[P(t-Bu)3]2, K3PO4, DMA, mw, 100 °C, 12−50%.

Table 1. Structures and Activities of Analogues 10.

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a

EC50 values are the average of three determinations; CV < 0.5.

b

Determined at 30 μM test compound wherein % max vehicle is 10−30%.

Among the N-aryl analogues synthesized and tested, only six compounds displayed functional activity below 10 μM. Subtle structural modifications resulted in complete loss of activity. For example, relative to the 2-pyridyl lead 8, the 3-pyridyl analogue 10b proved to be inactive. In addition, alternate hydrogen bond acceptors in this area of the molecule using various heterocycles such as a 2-pyrimidinyl (10h), 2-thiazolyl (10j), or 2-benzothiazolyl (10k) all proved deleterious for activity (EC50 > 10 μM). More direct structural changes within the 2-pyridyl scaffold were, however, well tolerated as exemplified by the trifluoromethyl-substituted analogue 10a. A greater departure from the 2-pyridyl motif via extension of hydrogen bond acceptor in the form of a 2-substituted phenyl scaffold was more successful (10c−g). In particular, compound 10e, which bears a 2-cyano substituent, was particularly interesting for its activity as a potentiator of the glutamate EC20 (>3-fold potency enhancement vs lead 8) but also its retained desirable physiochemical properties (cLog P = 3.1).23 Incorporation of more lipophilic modifications, such as a 2-chloro substituent (10d), was equally well tolerated with submicromolar potency (cLog P = 4.2). Larger polar substituents, such as a methyl ester (10f) and 2-methoxy (10c), were >5-fold less potent than 10e, yet comparable in activity relative to the lead compound 8. Interestingly, the 2-nitro analogue 10g was similarly active relative to 10e.

On the basis of the overall properties and significant structural departure from reported mGluR5 PAM chemotypes, we further characterized the in vitro pharmacological and DMPK profile of 10e, also identified as VU0364289. In a HEK293A rat mGluR5-expressing cell line, the raw calcium fluorescence trace using compound 10e alone at a concentration of 10 μM (Figure 3A) demonstrated no inherent mGluR5 agonism; however, a robust potentiation is observed upon addition of a submaximal EC20 concentration of glutamate. The concentration−response curve (CRC) for 10e in the presence or absence of glutamate is shown in Figure 3B, showing slight activation of mGluR5 alone only at concentrations above 30 μM. Next, we assessed the nature of the allosteric binding site for 10e in radioligand binding experiments with [3H]3-methoxy-PEPy. Interestingly, only a partial ca. 50% and incomplete displacement of the radioligand is observed at the highest compound concentration utilized (30 μM, data not shown), a concentration well above the functional EC50 of 10e (1.6 μM). These data suggest that 10e has insignificant interaction with the MPEP site and interacts with a distinct or overlapping allosteric site. Alternatively, it is conceivable that 10e is a low affinity ligand for the MPEP site and engenders high functional cooperativity as a PAM.24

Figure 3.

Figure 3

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(A) Effect of 10e glutamate response in HEK-293 cells expressing rat mGluR5. The dashed line represents the change in fluorescence of Fluo-4 in the presence of 0.1% DMSO in assay buffer. The solid line is the change in fluorescence of Fluo-4 in the presence of 10 μM 10e. All values are normalized to the change in fluorescence of Fluo-4 in the presence of a maximally effective concentration of glutamate (glutamate max). At the top of the figure, the bars indicate the addition of test compound (open bar), EC20 glutamate (gray bar, 0.25 μM), and EC80 glutamate (black bar, 1.25 μM). (B) Compound 10e potentiates mGluR5 activation by glutamate with an EC50 for potentiation of 1.6 μM. Compound 10e alone has no effect up to 10 μM, <10% at 30 μM.

To further understand the potential utility of 10e as an in vitro and possibly in vivo tool compound, selectivity versus the other seven mGluRs was examined employing a fold shift selectivity screen, wherein a glutamate CRC is generated in both the presence and the absence of the potentiator (Figure 4, EC50 fold shift represented for each receptor subtype). At a standard 10 μM concentration of 10e, a robust 12-fold shift for the glutamate CRC EC50 was observed for mGluR5 relative to the glutamate CRC EC50 in the absence of 10e, with no effect on the glutamate CRC for the remaining mGluRs1−4,6−8, thus demonstrating that 10e is highly selective for activation of the mGluR5 receptor.

Figure 4.

Figure 4

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mGluR fold shift selectivity screen with 10e at 10 μM.

Next, we turned to ascertaining the in vitro DMPK profile for 10e. Gratifyingly, 10e demonstrated a number of positive attributes from an in vitro DMPK perspective, which significantly improved upon the known mGluR5 PAM chemotypes studied to date in vivo (Figure 5): low to moderate binding to rat and human plasma (90 and 94%, respectively), acceptable transcellular permeability [>20 × 10−6 cm/s is preferred for central nervous system (CNS) targets], and moderate solubility in both a kinetic aqueous solubility screen (>0.03 mg/mL) and a nontoxic vehicle screen using 20% HP β-cyclodextrin (solution up to 2 mg/mL, microsuspension 3−5 mg/mL). The in vitro DMPK attributes for 10e represent a significant advance relative to existing mGluR5 PAMs CDPPB (2)9,10 and ADX47273 (4).13−15,25 Among the remaining DMPK parameters examined, 10e unfortunately displayed poor stability in both human and rat liver microsomes with less than 5% parent compound remaining after 60 min, thus precluding it from utility for oral dosing. As a result, we pursued alternate routes of administration, which would maximize systemic and CNS exposure to evaluate 10e as a new in vivo tool for mGluR5.

Figure 5.

Figure 5

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In vitro DMPK profile for 10e.

In light of the desirable physiochemical properties and the excellent in vitro profile identified for 10e, we performed a single dose in vivo screen to study the ability of 10e to reverse amphetamine-induced hyperlocomotion in rats (Figure 6). Indeed, after an ip administration at 56.6 mg/kg in 20% HP β-cyclodextrin as vehicle, 10e showed robust and sustained efficacy in this preclinical model. In addition, we have evaluated open field locomotor activity using 10e dosed alone at 56.6 mg/kg, and no sedation or abnormal behavior was observed.26 Importantly, 10e shows similar positive effects in this model as previously noted with mGluR5 PAMs CDPPB5,12 and ADX-472737 as well as other clinically relevant antipsychotic agents. Although the minimal effective dose for VU0364289 (10e) in this model remains to be seen, relative to CDPPB12 and ADX-47273,7 at 56.6 mg/kg, 10e is efficacious at similar or in the case of ADX-47273 at ∼2× lower doses. These data provide further preclinical validation of the selective activation of mGluR5, by positive allosteric modulation, for the treatment of schizophrenia and other psychiatric disorders.

Figure 6.

Figure 6

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Compound 10e (VU0364289) reverses amphetamine-induced hyperlocomotor activity in rats without causing sedation. Rats were pretreated for 30 min with vehicle or a 56.6 mg/kg dose of 10e ip in 20% HP β-cyclodextrin. All rats received an injection of 1 mg/kg sc amphetamine at 60 min, and locomotor activity was measured for an additional 60 min. Each point represents the mean of 12−14 rats. The error bars represent SEM and are absent when less than the size of the point. Abscissa, time in minutes; ordinate, ambulations or total beam breaks per 5 min intervals; #P < 0.05 vs veh + amphetamine control group, Dunnett's test.

In conclusion, we have demonstrated that from a structurally nonrelated MPEP-based mGluR5 NAM series of N-aryl piperazines, a similarly potent PAM can readily be identified through a “molecular switch” to generate for the first time a useful in vivo tool for the mGluR5 PAM field, which is active in a preclinically validated model known to be responsive with current antipsychotic therapies. Because of the inherent properties of this class of compounds, it may now be possible through further careful pharmacological characterization to pave the way to a deeper understanding of the pharmacokinetic−pharmacodynamic relationship for this molecular target in multiple models, including cognition and transgenic models, as they relate to psychiatric disease. Toward this goal, a more detailed investigation of the metabolite profile and exposure−effect relationship of VU0364289 (10e) across a range of doses is ongoing. In addition, a greater understanding of the molecular basis for the piperazine amide “molecular switch” in the context of known receptor mutant pharmacology in conjunction with radioligand binding studies as it relates to the established MPEP binding site will also be a major focus for this unique mGluR5 PAM chemotype and will be reported in due course.

Acknowledgments

We thank Kiran Gogi from the Vanderbilt HTS Screening Lab for assistance in conducting the mGluR5 HTS screen.

Supporting Information Available

Experimental procedures and analytical data for compounds 8 and 10e. This material is available free of charge via the Internet at http://pubs.acs.org.

This paper was published on the Web on August 13, 2010, with an error in Figure 1. The corrected version including revised Supporting Information containing additional information was reposted on September 20, 2010.

We thank the NIH National Institute of Neurological Disorders and Stroke (NINDS #5R01 NS031373-15) and the National Institute of Mental Health (NIMH #R01 MH073676-04) for support of this program.

Funding Statement

National Institutes of Health, United States

Supplementary Material

ml100181a_si_001.pdf (187.7KB, pdf)

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Supplementary Materials

ml100181a_si_001.pdf (187.7KB, pdf)

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