Recommendations to standardize patients' follow-up after interventional procedures in chronic pain treatment: A Delphi study.

OBJECTIVE: To determine, using the Delphi method, standardized recommendations for the follow-up of patients undergoing an interventional procedure for the treatment of chronic pain in Spain. METHODS: First, a systematic literature review was performed to identify the literature on the management of patients with chronic pain undergoing interventional techniques; subsequently, a two-round Delphi survey with 108 questions was conducted. The questionnaire was validated by a Scientific Committee (5 experts) and sent to 47 experts specialized in chronic pain. "Consensus" or "intermediate consensus" was determined when ≥ 75% or < 75% to ≥ 65% of the experts selected the same answer for each item, respectively. Then, a face-to-face deliberation process was held with the Scientific Committee to analyze and discuss the results. RESULTS: The questionnaire was completed by 24 panelists (51%). Consensus was reached on 88.4% of the questions. The panelists identified pain, drug consumption, and quality of life as essential variables in the follow-up of patients with chronic pain. Consensus was reached on most of the scales/questionnaires to be used in measuring outcomes during follow-up, except for psychological status. Regarding the follow-up frequency, in radicular spinal chronic pain, a consensus was reached on the first visit 1-2 months after the intervention, during the first year, at 1, 3, 6, and 12 months, and then every 6 months thereafter. For non-radicular spinal chronic pain, the first visit 1-2 months after surgery was agreed upon, however, there was no consensus on follow-up during the first year. For non-spinal chronic pain, consensus was reached regarding the first visit at 1-2 months after surgery and during the first year at 1, 3, 6, and 12 months. No consensus was reached on follow-up frequency for oncological chronic pain. After receiving a permanent neurostimulator implant for chronic pain, the first visit was agreed upon at 1-3 weeks, during the first year, at 2 weeks, 1, 3, 6, and 12 months, and after, every 6 months. For intrathecal infusion, it was agreed that the first visit should occur during the first month, and thereafter whenever the pump requires a refill. CONCLUSIONS: These findings provide recommendations in relation to the frequency of follow-up and the scales to be used with chronic pain patients undergoing interventional techniques in Spain.

A modified Delphi survey on the signs and symptoms of low back pain: indicators for an interventional management approach.

BACKGROUND: Low back pain (LBP) symptoms and signs are nonspecific. If required, diagnostic blocks may find the source of pain, but indicators of suspect diagnosis must be defined to identify anatomical targets. OBJECTIVE: To reach a consensus from an expert panel on the indicators for the most common causes of LBP. MATERIAL AND METHODS: A 3-round (2 telematic and 1 face-to-face) modified Delphi survey with a questionnaire on 78 evidence-based indicators of 7 LBP etiologies was completed by 23 experts. RESULTS: 98.7% of the questionnaire was consensuated. The most accepted indicators were for zygapophysial joint pain, painful ipsilateral paravertebral palpation, worsening with trunk extension, paravertebral musculature spasm on the affected articulation, and referred pain above the knee, without radicular pattern. For sacroiliac joint pain, unilateral pain when seating, with at least 3 described provoking tests: Approximation; gapping; Patrick's; Gaenslen's; thigh thrust; Fortin finger; and Gillet's tests. For discogenic pain, midline pain that may be provoked by pressure on the spinal processes at the affected level; for quadratus lumborum muscle, painful palpation on both the L1 level paravertebral region, referred to iliac crest, and the iliac crest, referred to greater trochanter. For iliopsoas muscle, pain elicited by thigh flexion, referred to buttock, inguinal region, and anterior thigh. For pyramidal muscle, pain while sitting on the affected side and positive Freiberg's test. For radicular pain, paresthesias and positive Lassègue's test at 60°. CONCLUSION: Seventy-seven diagnostic suspect indicators of LBP conditions were consensuated. These may facilitate conservative or interventional pain management decision-making.

Discovery of 6,7-Dihydropyrazolo[1,5-a]pyrazin-4(5H)-one Derivatives as mGluR2 Negative Allosteric Modulators with In Vivo Activity in a Rodent's Model of Cognition.

Allosteric modulators of the metabotropic group II receptors, mGluR2 and mGluR3, have been widely explored due to their ability to modulate cognitive and neurological functions in mood disorders, although none have been approved yet. In our search for new and selective mGluR2 negative allosteric modulators (NAMs), series of 6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one derivatives were identified from our published series of 1,3,5-trisubstituted pyrazoles. SAR evolution of the initial hit resulted in 100-fold improvement in the mGluR2 NAM potency and subsequent selection of compound 11 based on its overall profile, including selectivity and ADMET properties. Further pharmacokinetic-pharmacodynamic (PK-PD) relationship built showed that compound 11 occupied the mGluR2 receptor in a dose-dependent manner. Additionally, the compound revealed in vivo activity in V-maze as a model of cognition from a dose of 0.32 mg/kg. Compound 11 was selected to be evaluated further.

Pharmacological characterization of JNJ-40068782, a new potent, selective, and systemically active positive allosteric modulator of the mGlu2 receptor and its radioligand [3H]JNJ-40068782.

Modulation of the metabotropic glutamate type 2 (mGlu2) receptor is considered a promising target for the treatment of central nervous system diseases such as schizophrenia. Here, we describe the pharmacological properties of the novel mGlu2 receptor positive allosteric modulator (PAM) 3-cyano-1-cyclopropylmethyl-4-(4-phenyl-piperidin-1-yl)-pyridine-2(1H)-one (JNJ-40068782) and its radioligand [(3)H]JNJ-40068782. In guanosine 5'-O-(3-[(35)S]thio)triphosphate binding, JNJ-40068782 produced a leftward and upward shift in the glutamate concentration-effect curve at human recombinant mGlu2 receptors. The EC50 of JNJ-40068782 for potentiation of an EC20-equivalent concentration of glutamate was 143 nM. Although JNJ-40068782 did not affect binding of the orthosteric antagonist [(3)H]2S-2-amino-2-(1S,2S-2-carboxycyclopropyl-1-yl)-3-(xanth-9-yl)propanoic acid (LY-341495), it did potentiate the binding of the agonist [(3)H](2S,2'R,3'R)-2-(2',3'-dicarboxylcyclopropyl)glycine (DCG-IV), demonstrating that it can allosterically affect binding at the agonist recognition site. The binding of [(3)H]JNJ-40068782 to human recombinant mGlu2 receptors in Chinese hamster ovary cells and rat brain receptors was saturable with a KD of ∼10 nM. In rat brain, the anatomic distribution of [(3)H]JNJ-40068782 was consistent with mGlu2 expression previously described and was most abundant in cortex and hippocampus. The ability of structurally unrelated PAMs to displace [(3)H]JNJ-40068782 suggests that PAMs may bind to common determinants within the same site. It is noteworthy that agonists also increased the binding affinity of [(3)H]JNJ-40068782. JNJ-40068782 influenced rat sleep-wake organization by decreasing rapid eye movement sleep with a lowest active dose of 3 mg/kg PO. In mice, JNJ-40068782 reversed phencyclidine-induced hyperlocomotion with an ED50 of 5.7 mg/kg s.c. Collectively, the present data demonstrate that JNJ-40068782 has utility in investigating the potential of mGlu2 modulation for the treatment of diseases characterized by disturbed glutamatergic signaling and highlight the value of [(3)H]JNJ-40068782 in exploring allosteric binding.

Long-term safety of spinal cord stimulation systems in a prospective, global registry of patients with chronic pain.

Aim: The availability of long-term (>2 years) safety outcomes of spinal cord stimulation (SCS) remains limited. We evaluated safety in a global SCS registry for chronic pain. Methods: Participants were prospectively enrolled globally at 79 implanting centers and followed out to 3 years after device implantation. Results: Of 1881 participants enrolled, 1289 received a permanent SCS implant (1776 completed trial). The annualized rate of device explant was 3.5% (all causes), and 1.1% due to inadequate pain relief. Total incidence of device explantation >3 years was 7.6% (n = 98). Of these, 32 subjects (2.5%) indicated inadequate pain relief as cause for removal. Implant site infection (11 events) was the most common device-related serious adverse event (<1%). Conclusion: This prospective, global, real-world study demonstrates a high-level of safety for SCS with low rate of explant/serious adverse events. Clinical Trial Registration: NCT01719055 (ClinicalTrials.gov).

New positive allosteric modulators of the metabotropic glutamate receptor 2 (mGluR2): identification and synthesis of N-propyl-8-chloro-6-substituted isoquinolones.

A series of N-propyl-8-chloro-6-substituted isoquinolones was identified as positive allosteric modulators of metabotropic glutamate receptor 2 (mGluR2 PAM) via high throughput screening (HTS). The subsequent synthesis and initial SAR exploration that led to the identification of compound 28 is described.

Scaffold Hopping to Imidazo[1,2-a]pyrazin-8-one Positive Allosteric Modulators of Metabotropic Glutamate 2 Receptor.

Glutamate hyperfunction is implicated in multiple neurological and psychiatric diseases. Activation of the mGlu2 receptor results in reduced glutamate release and decreased excitability representing a promising novel therapeutic agent for the treatment of disorders such as epilepsy, schizophrenia, mood, anxiety, and other neuropsychiatric disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs from different chemical series. Herein, the discovery and optimization of a novel series of imidazopyrazinone mGlu2 PAMs are reported. This new scaffold originated from computational searching of fragment databases and comparison with our previously explored scaffolds. Optimization guided by our robust understanding of SAR from former series led to potent, selective, and brain-penetrant compounds.

Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor.

Imidazo[1,2-a]pyridines were identified via their shape and electrostatic similarity as novel positive allosteric modulators of the metabotropic glutamate 2 receptor. The subsequent synthesis and SAR are described. Potent, selective and metabolically stable compounds were found representing a promising avenue for current further studies.

Spiro-oxindole Piperidines and 3-(Azetidin-3-yl)-1H-benzimidazol-2-ones as mGlu2 Receptor PAMs.

Starting from two weak mGlu2 receptor positive allosteric modulator (PAM) HTS hits (4 and 5), a molecular hybridization strategy resulted in the identification of a novel spiro-oxindole piperidine series with improved activity and metabolic stability. Scaffold hopping around the spiro-oxindole core identified the 3-(azetidin-3-yl)-1H-benzimidazol-2-one as bioisoster. Medicinal chemistry optimization of these two novel chemotypes resulted in the identification of potent, selective, orally bioavailable, and brain penetrant mGluR2 PAMs.

mGluR2 positive allosteric modulators: an updated patent review (2013-2018).

INTRODUCTION: Positive allosteric modulation of mGlu2 has attracted much interest as an alternative approach to classical orthosteric receptor activation. Two mGlu2 PAMS have advanced into the clinic. The results obtained in schizophrenia and MDD phase 2 clinical trials have tempered the high expectations put on selective mGlu2 receptor activation for treating these conditions; nevertheless, the search for novel therapeutic indications and novel chemotypes continues to be an active field of research. AREAS COVERED: 2013-2018 patent literature on mGlu2 receptor PAMs. EXPERT OPINION: After a decade of intensive research, the mGlu2 PAM field has seen a deceleration in the last five years. Negative phase 2 schizophrenia clinical trials with JNJ-40411813 and AZD8529 seem to have tempered the high expectations of the scientific community on the utility of mGlu2 PAMs for the treatment of schizophrenia. Nevertheless, novel therapeutic indications continue to be explored and AZD8529 is currently in a phase 2 study for smoking cessation. The advances in medicinal chemistry and in pharmacology, with novel indications such as epilepsy, have set the stage in the field of mGlu2 receptor PAMs. Ongoing preclinical and clinical studies will contribute to define their optimal therapeutic indication and potential to become novel therapeutic agents.

Computationally Guided Identification of Allosteric Agonists of the Metabotropic Glutamate 7 Receptor.

The metabotropic glutamate 7 (mGlu7) receptor belongs to the group III of mGlu receptors. Since the mGlu7 receptor can control excitatory neurotransmission in the hippocampus and cortex, modulation of the receptor may have therapeutic benefit in several CNS diseases. However, mGlu7 remains relatively unexplored among the eight known mGlu receptors partly because of the limited availability of tool compounds to interrogate its potential therapeutic utility. Here we report the discovery of a new class of mGlu7 allosteric agonists. Hits originating from virtual screening were followed up with further analogue searching and screening, leading to a novel series of mGlu7 allosteric agonists. Guided by docking into a structural model of the mGlu7 receptor the initial hit 5 was successfully optimized to analogues with comparable potencies and more attractive drug-like attributes than AMN082.

Covalent Allosteric Probe for the Metabotropic Glutamate Receptor 2: Design, Synthesis, and Pharmacological Characterization.

Covalent labeling of G protein-coupled receptors (GPCRs) by small molecules is a powerful approach to understand binding modes, mechanism of action, pharmacology, and even facilitate structure elucidation. We report the first covalent positive allosteric modulator (PAM) for a class C GPCR, the mGlu2 receptor. Three putatively covalent mGlu2 PAMs were designed and synthesized. Pharmacological characterization identified 2 to bind the receptor covalently. Computational modeling combined with receptor mutagenesis revealed T7917.29×30 as the likely position of covalent interaction. We show how this covalent ligand can be used to characterize the PAM binding mode and that it is a valuable tool compound in studying receptor function and binding kinetics. Our findings advance the understanding of the mGlu2 PAM interaction and suggest that 2 is a valuable probe for further structural and chemical biology approaches.

Imprisonment, Social Support, and Desistance: A Theoretical Approach to Pathways of Desistance and Persistence for Imprisoned Men.

Desistance should be the main ground for reentry policies for imprisoned offenders. However, theories on desistance are diverse, and they disagree about the key factors related to the origin, maintenance, and failures of the desistance process. This research considers three main theories of desistance-control, cognitive transformation, and strain-social support-to explain desistance in a sample of imprisoned men in Spain. The main finding of the research is that strain-social support theory may be of primary importance for understanding desistance because of its capacity to explain processes of change that begin during imprisonment and that continue upon release.

Discovery and Kinetic Profiling of 7-Aryl-1,2,4-triazolo[4,3-a]pyridines: Positive Allosteric Modulators of the Metabotropic Glutamate Receptor 2.

We report the synthesis and biological evaluation of a series of 7-aryl-1,2,4-triazolo[4,3-a]pyridines with mGlu2 positive allosteric modulator (PAM) activity and affinity. Besides traditional in vitro parameters of potency and affinity, kinetic parameters kon, koff and residence time (RT) were determined. The PAMs showed various kinetic profiles; kon values ranged over 2 orders of magnitude, whereas RT values were within a 10-fold range. Association rate constant kon was linearly correlated to affinity. Evaluation of a short, medium, and long RT compound in a label-free assay indicated a correlation between RT and functional effect. The effects of long RT compound 9 on sleep-wake states indicated long RT was translated into sustained inhibition of rapid eye movement (REM) in vivo. These results show that affinity-only driven selection would have resulted in mGlu2 PAMs with high values for kon but not necessarily optimized RT, which is key to predicting optimal efficacy in vivo.

Molecular mechanism of positive allosteric modulation of the metabotropic glutamate receptor 2 by JNJ-46281222.

BACKGROUND AND PURPOSE: Allosteric modulation of the mGlu2 receptor is a potential strategy for treatment of various neurological and psychiatric disorders. Here, we describe the in vitro characterization of the mGlu2 positive allosteric modulator (PAM) JNJ-46281222 and its radiolabelled counterpart [(3) H]-JNJ-46281222. Using this novel tool, we also describe the allosteric effect of orthosteric glutamate binding and the presence of a bound G protein on PAM binding and use computational approaches to further investigate the binding mode. EXPERIMENTAL APPROACH: We have used radioligand binding studies, functional assays, site-directed mutagenesis, homology modelling and molecular dynamics to study the binding of JNJ-46281222. KEY RESULTS: JNJ-46281222 is an mGlu2 -selective, highly potent PAM with nanomolar affinity (KD = 1.7 nM). Binding of [(3) H]-JNJ-46281222 was increased by the presence of glutamate and greatly reduced by the presence of GTP, indicating the preference for a G protein bound state of the receptor for PAM binding. Its allosteric binding site was visualized and analysed by a computational docking and molecular dynamics study. The simulations revealed amino acid movements in regions expected to be important for activation. The binding mode was supported by [(3) H]-JNJ-46281222 binding experiments on mutant receptors. CONCLUSION AND IMPLICATIONS: Our results obtained with JNJ-46281222 in unlabelled and tritiated form further contribute to our understanding of mGlu2 allosteric modulation. The computational simulations and mutagenesis provide a plausible binding mode with indications of how the ligand permits allosteric activation. This study is therefore of interest for mGlu2 and class C receptor drug discovery.

Discovery of 8-Trifluoromethyl-3-cyclopropylmethyl-7-[(4-(2,4-difluorophenyl)-1-piperazinyl)methyl]-1,2,4-triazolo[4,3-a]pyridine (JNJ-46356479), a Selective and Orally Bioavailable mGlu2 Receptor Positive Allosteric Modulator (PAM).

Positive allosteric modulators of the metabotropic glutamate 2 receptor have generated great interest in the past decade. There is mounting evidence of their potential as therapeutic agents in the treatment of multiple central nervous system disorders. We have previously reported substantial efforts leading to potent and selective mGlu2 PAMs. However, finding compounds with the optimal combination of in vitro potency and good druglike properties has remained elusive, in part because of the hydrophobic nature of the allosteric binding site. Herein, we report on the lead optimization process to overcome the poor solubility inherent to the advanced lead 6. Initial prototypes already showed significant improvements in solubility while retaining good functional activity but displayed new liabilities associated with metabolism and hERG inhibition. Subsequent subtle modifications efficiently addressed those issues leading to the identification of compound 27 (JNJ-46356479). This new lead represents a more balanced profile that offers a significant improvement on the druglike attributes compared to previously reported leads.

Discovery of new tetracyclic tetrahydrofuran derivatives as potential broad-spectrum psychotropic agents.

A series of novel tetracyclic tetrahydrofuran derivatives was prepared and evaluated for its potential psychotropic properties. In vitro affinities for multiple dopaminergic, serotonergic, alpha-adrenergic, and histamine receptors and for the norepinephrine transporter as well as the ED(50) values obtained in some in vivo assays for antipsychotic, anxiolytic, and antidepressant potential are reported. Compounds (-)-1, (-)-8d, and (+)-8d have been identified as potential broad-spectrum psychotropic agents.

Discovery of a new series of centrally active tricyclic isoxazoles combining serotonin (5-HT) reuptake inhibition with alpha2-adrenoceptor blocking activity.

The synthesis and pharmacology of a new series of 3-piperazinylmethyl-3a,4-dihydro-3H-[1]benzopyrano[4,3-c]isoxazoles that combine central serotonin (5-HT) reuptake inhibition with alpha(2)-adrenoceptor blocking activity is described as potential antidepressants. Four compounds were selected for further evaluation, and the combination of both activities was found to be stereoselective, residing mainly in one enantiomer. Reversal of the loss of righting induced by the alpha(2)-agonist medetomidine in rats confirmed the alpha(2)-adrenoceptor blocking activity in vivo and also demonstrated CNS penetration. Antagonism of p-chloroamphetamine (pCA)-induced excitation as well as blockade of the neuronal 5-HT depletion induced by p-CA administration in rats confirmed their ability to block the central 5-HTT, even after oral administration. Replacement of the oxygen atom at the 5-position of the tricyclic scaffold by a nitrogen or a carbon atom, as well as O-substitution at position 7, led also to active compounds, both in vitro and in vivo.

Synthesis of 2-N,N-dimethylaminomethyl-2,3,3a,12b-tetrahydrodibenzo[b,f]furo[2,3-d]oxepine derivatives as potential anxiolytic agents. Part 2: substitutions by methyl groups on the tetrahydrofuran ring.

New synthesis approaches that have led to a series of novel tetrahydrodibenzo[b,f]furo[2,3-d]oxepine derivatives are described. A systematic synthetic approach for the introduction of small carbon substituents (methyl groups) around the tetrahydrofuran moiety of tetrahydrodibenzo[b,f]furo[2,3-d]oxepine derivatives is reported. Preliminary pharmacological data of the newly synthesised compounds are also communicated.