A New Pharmacophore Model for the Design of Sigma-1 Ligands Validated on a Large Experimental Dataset

The recent publication of the σ1R crystal structure is an important cornerstone for the derivation of more accurate activity prediction models. We report here a comparative study involving a set of more than 25,000 structures from our internal database that had been screened for σ1R affinity. Using the recently published crystal structure, 5HK1, two new pharmacophore models were generated. The first one, 5HK1–Ph.A, was obtained by an algorithm that identifies the most important receptor-ligand interactions including volume restrictions enforced by the atomic structure of the recognition site. The second, 5HK1–Ph.B, resulted from a manual edition of the first one by the fusion of two hydrophobic (HYD) features. Finally, we also docked the database using a high throughput docking technique and scored the resulting poses with seven different scoring functions. Statistical performance measures were obtained for the two models, comparing them with previously published σ1R pharmacophores (Hit Rate, sensitivity, specificity, and Receiver Operator Characteristic) and 5HK1–Ph.B emerged as the best one in discriminating between active and inactive compounds, with a ROC-AUC value above 0.8 and enrichment values above 3 at different fractions of screened samples. 5HK1–Ph.B also showed better results than the direct docking, which may be due to the rigidity of the crystal structure in the docking process (i.e., feature tolerances in the pharmacophore model). Additionally, the impact of the HYD interactions and the penalty for desolvating ligands with polar atoms may be not adequately captured by scoring functions, whereas HYD groups filling up such regions of the binding site are entailed in the pharmacophore model. Altogether, using annotated data from a large and diverse compound collection together with crystal structure information provides a sound basis for the generation and validation of predictive models to design new molecules

The effect of food on tramadol and celecoxib bioavailability following oral administration of Co-Crystal of Tramadol-Celecoxib (CTC): a randomised, open label, single-dose, crossover study in healthy volunteers

ackground and Objective Co-Crystal of Tramadol-Celecoxib (CTC), in development for the treatment of moderate to severe acute pain, is a first-in-class co-crystal containing a 1:1 molecular ratio of two active pharmaceutical ingredients; rac- tramadol·HCl and celecoxib. This randomised, open-label, crossover study compared the bioavailability of both components after CTC administration under fed and fasting conditions. Methods Healthy adults received single doses of 200 mg CTC under both fed and fasting conditions (separated by a 7-day washout). Each dose of CTC was administered orally as two 100 mg tablets, each containing 44 mg tramadol·HCl and 56 mg celecoxib. In the fed condition, a high-fat, high-calorie meal [in line with recommendations by the US Food and Drug Administration (FDA)] was served 30 min before CTC administration. Tramadol, O-desmethyltramadol and celecoxib plasma concentrations were measured pre- and post-dose up to 48 h. Pharmacokinetic parameters were calculated using non-compartmental analysis. Safety was also assessed. Results Thirty-six subjects (18 female/18 male) received one or both doses of CTC; 33 provided evaluable pharmacokinetic data under fed and fasting conditions. For tramadol and O-desmethyltramadol, fed-to-fasting ratios of geometric least-squares means and corresponding 90% confidence interval (CI) values for maximum plasma concentration (Cmax) and extrapolated area under the plasma concentration-time curve to infinity (AUC∞) were within the pre-defined range for comparative bio- availability (80-125%). For celecoxib, Cmax and AUC∞ fed-to-fasting ratios (90% CIs) were outside this range, at 130.91% (116.98-146.49) and 129.34% (121.78-137.38), respectively. The safety profile of CTC was similar in fed and fasting conditions. Conclusions As reported for standard-formulation celecoxib, food increased the bioavailability of celecoxib from single-dose CTC. Food had no effect on tramadol or O-desmethyltramadol bioavailability

Co-crystal of Tramadol-Celecoxib in Patients with Moderate to Severe Acute Post-surgical Oral Pain: A Dose-Finding, Randomised, Double-Blind, Placebo- and Active-Controlled, Multicentre, Phase II Trial

Background Co-crystal of tramadol-celecoxib (CTC), containing equimolar quantities of the active pharmaceu- tical ingredients (APIs) tramadol and celecoxib (100 mg CTC = 44 mg rac-tramadol hydrochloride and 56 mg celecoxib), is a novel API-API co-crystal for the treatment of pain. We aimed to establish the effective dose of CTC for treating acute pain following oral surgery. Methods A dose-finding, double-blind, randomised, pla- cebo- and active-controlled, multicentre (nine Spanish hospitals), phase II study (EudraCT number: 2011-002778- 21) was performed in male and female patients aged C 18 years experiencing moderate to severe pain following extraction of two or more impacted third molars requiring bone removal. Eligible patients were randomised via a computer-generated list to receive one of six single-dose treatments (CTC 50, 100, 150, 200 mg; tramadol 100 mg; and placebo). The primary efficacy endpoint was the sum of pain intensity difference (SPID) over 8 h assessed in the per-protocol population. Results Between 10 February 2012 and 13 February 2013, 334 patients were randomised and received study treat- ment: 50 mg (n = 55), 100 mg (n = 53), 150 mg (n = 57), or 200 mg (n = 57) of CTC, 100 mg tramadol (n = 58), or placebo (n = 54). CTC 100, 150, and 200 mg showed significantly higher efficacy compared with placebo and/or tramadol in all measures: SPID (0-8 h) (mean [standard deviation]): - 90 (234), - 139 (227), - 173 (224), 71 (213), and 22 (228), respectively. The proportion of patients experiencing treatment-emergent adverse events was lower in the 50 (12.7% [n = 7]), 100 (11.3% [n = 6]), and 150 (15.8% [n = 9]) mg CTC groups, and similar in the 200 mg (29.8% [n = 17]) CTC group, compared with the tramadol group (29.3% [n = 17]), with nausea, dizzi- ness, and vomiting the most frequent events. Conclusion Significant improvement in the benefit-risk ratio was observed for CTC (doses C 100 mg) over tra- madol and placebo in the treatment of acute pain following oral surgery

Neither acute nor chronic exposure to a naturalistic (predator) stressor influences the interleukin-1beta system, tumor necrosis factor-alpha, transforming growth factor-beta1, and neuropeptide mRNAs in specific brain regions

Physical (neurogenic) stressors may influence immune functioning and interleukin-1β (IL-1β) mRNA levels within several brain regions. The present study assessed the effects of an acute or repeated naturalistic, psychogenic stressor (predator exposure) on brain cytokine and neuropeptide mRNAs. Acute predator (ferret) exposure induced stress-like behavioral effects, including elicitation of a startle response and reduced exploratory behaviors; these responses diminished after 30 sessions. Moreover, acute and repeated predator exposure, like acute restraint stress, increased plasma corticosterone levels measured 5 min later, but not 2 h after stressor exposure. In contrast, none of the stressors used influenced IL-1β, IL-1 receptor antagonist, IL-1 receptor type I, IL-1 receptor accessory proteins I and II, or tumor necrosis factor-α mRNA levels in the prefrontal cortex, amygdala, hippocampus, or hypothalamus. Likewise, there were no stressor effects on transforming growth factor-β1, neuropeptide Y, glycoprotein 130, or leptin receptor mRNAs in brain regions. Thus, the naturalistic/psychogenic stressor used does not affect any of the brain cytokine component mRNAs studied. It is suggested that this type of stressor activates homeostatic mechanisms (e.g., glucocorticoid release), which act to preclude brain cytokine alterations that would otherwise favor neuroinflammatory/neuroimmunological responses and the consequent increase of brain sensitivity to neurotoxic and neurodegenerative processes