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Bispecific sigma-1 receptor antagonism and mu-opioid receptor partial agonism:WLB-73502,an analgesic with improved efficacy and safety profile compared to strong opioids

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Acta Pharmaceutica Sinica B 2023年第1期13卷 82-99页

作者： Alba Vidal-Torres Begoña Fernández-Pastor Mónica García Eva Ayet Anna Cabot Javier Burgueño Xavier Monroy Bertrand Aubel Xavier Codony Luz Romero Rosalía Pascual Maria Teresa Serafini Gregorio Encina Carmen Almansa Daniel Zamanillo Manuel Merlos josémiguel vela WeLab Barcelona Parc Cientific de BarcelonaBarcelona 08028Spain

Opioids are the most effective painkillers,but their benefit-risk balance often hinder their therapeutic use.WLB-73502 is a dual,bispecific compound that binds sigma-1(S1R)and mu-opioid(MOR)receptors.WLB-73502 is an antagonist at the S1R.It behaved as a partial MOR agonist at the G-protein pathway and produced no/unsignificantβ-arrestin-2 recruitment,thus demonstrating low intrinsic efficacy on MOR at both signalling pathways.Despite its partial MOR agonism,WLB-73502exerted full antinociceptive efficacy,with potency superior to morphine and similar to oxycodone against nociceptive,inflammatory and osteoarthritis pain,and superior to both morphine and oxycodone against neuropathic pain.WLB-73502 crosses the blood-brain barrier and binds brain S1R and MOR to an extent consistent with its antinociceptive effect.Contrary to morphine and oxycodone,tolerance to its antinociceptive effect did not develop after repeated 4-week administration.Also,contrary to opioid comparators,WLB-73502 did not inhibit gastrointestinal transit or respiratory function in rats at doses inducing full efficacy,and it was devoid of proemetic effect(retching and vomiting)in ferrets at potentially effective doses.WLB-73502 benefits from its bivalent S1R antagonist and partial MOR agonist nature to provide an improved antinociceptive and safety profile respect to strong opioid therapy.

关键词： WLB-73502 Sigma-1 receptor Mu-opioid receptor Biased agonist Analgesic activity Chronic pain Neuropathic pain Safety

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Animal models used to study direct peripheral nerve repair: a systematic review

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Neural Regeneration Research 2020年第3期15卷 491-502页

作者： Francisco Javier vela Guadalupe Martínez-Chacón Alberto Ballestín joséLuis Campos Francisco miguel Sánchez-Margallo Elena Abellán Department of Microsurgery Jesús Usón Minimally Invasive Surgery CentreCáceresSpain Scientific Director Jesús Usón Minimally Invasive Surgery CentreCáceresSpain

Objective:Peripheral nerve repair is required after traumatic injury.This common condition represents a major public health problem worldwide.Recovery after nerve repair depends on several factors,including the severity of the injury,the nerve involved,and the surgeon’s technical skills.Despite the precise microsurgical repair of nerve lesions,adequate functional recovery is not always achieved and,therefore,the regeneration process and surgical techniques are still being studied.Pre-clinical animal models are essential for this research and,for this reason,the focus of the present systematic review(according to the PRISMA statement)was to analyze the different animal models used in pre-clinical peripheral nerve repair studies.Data sources:Original articles,published in English from 2000 to 2018,were collected using the Web of Science,Scopus,and PubMed databases.Data selection:Only preclinical trials on direct nerve repair were included in this review.The articles were evaluated by the first two authors,in accordance with predefined data fields.Outcome measures:The primary outcomes included functional motor abilities,daily activity and regeneration rate.Secondary outcomes included coaptation technique and animal model.Results:This review yielded 267 articles,of which,after completion of the screening,49 studies were analyzed.There were 1425 animals in those 49 studies,being rats,mice,guinea pigs,rabbits,cats and dogs the different pre-clinical models.The nerves used were classified into three groups:head and neck(11),forelimb(8)and hindlimb(30).The techniques used to perform the coaptation were:microsuture(46),glue(12),laser(8)and mechanical(2).The follow-up examinations were histology(43),electrophysiological analysis(24)and behavioral observation(22).Conclusion:The most widely used animal model in the study of peripheral nerve repair is the rat.Other animal models are also used but the cost-benefit of the rat model provides several strengths over the others.Suture techniques are currently the first option for n

关键词： nerve microsurgery peripheral nerve regeneration repair reconstruction direct nerve repair animal model coaptation PRISMA systematic review

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Reactivity of Indoles through the Eyes of a Charge-Transfer Partitioning Analysis

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物理化学学报 2018年第6期34卷 692-698页

作者： OROZCO-VALENCIA Ulises GáZQUEZ josé L. vela Alberto Departamento de Quimica Centro de Investigacion y de Estudios Avanzados Av. Instituto Politecnico Nacional 2508 Colonia San Pedro Zacatenco Ciudad de Mexico 07360 Mexico. Departamento de Quimica Universidad Autonoma Metropolitana-Iztapalapa

A global and local charge transfer partitioning model,based on the cornerstone theory developed by Robert G.Parr and Robert G.Pearson,which introduces two charge transfer channels(one for accepting electrons(electrophilic) and another for donating(nucleophilic)),is applied to the reaction of a set of indoles with 4,6-dinitrobenzofuroxan.The global analysis indicates that the prevalent electron transfer mechanism in the reaction is a nucleophilic one on the indoles,i.e.,the indoles under consideration transfer electrons to 4,6-dinitrobenzofuroxan.Evaluating the reactivity descriptorswith exchange-correlation functionals including exact exchange(global hybrids) yields slightly better correlations than those obtained with generalized gradient-approximated functionals;however,the trends are preserved.Comparing the trend obtained with the number of electrons donated by the indoles,and predicted by the partitioning model,with that observed experimentally based on the measured rate constants,we propose that the number of electrons transferred through this channel can be used as a nucleophilicity scale to order the reactivity of indoles towards 4,6-dinitrobenzofuroxan.This approach to obtain reactivity scales has the advantage of depending on the intrinsic properties of the two reacting species;therefore,it opens the possibility that the same group of molecules may show different reactivity trends depending on the species with which they are reacting.The local model allows systematic incorporation of the reactive atoms based on the their decreasing condensed Fukui functions,and the correlations obtained by increasing the number of reactive atoms participating in the local analysis of the transferred nucleophilic charge improve,reaching an optimal correlation,which in the present case indicates keeping three atoms from the indoles and two from 4,6-dinitrobenzofuroxan.The atoms selected by this procedure provide valuable information about the local reactivity of the indoles.We further show that this information about the m

关键词： Chemical reactivity Conceptual DFT Charge transfer Nucleophilicity Indoles Transition state prediction

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Thermodynamic Dual Descriptor

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物理化学学报 2018年第6期34卷 683-691页

作者： FRANCO-PéREZ Marco GáZQUEZ josé L. AYERS Paul W. vela Alberto Departamento de Quimica Universidad Aut6noma Metropolitana-Iztapalapa Av. San Rafael Atlixco 186 Ciudad de Mexico 09340 Mexico. Department of Chemistry McMaster University Hamilton Ontario L8S 4M1 Canada. Departamento de Quimica Centro

A new definition of the dual descriptor,namely,thethermodynamic dual descriptor,is developed within the grand canonicalpotential formalism.This new definition is formulated to describe the same △f_r(r)=β/2C[f^+(r)-f^-(r)](C>0) physical phenomenon as the original definition proposed by Morell,Grand,and Toro-Labbé(J.Phys.Chem.A2005,109,205),which is characterized by a second-order response of the electron density towards an electron flux.To formulate the new definition,we performed two successive partial derivatives of the average electron density,one with respect to the average number of electrons,and the other with respect to the chemical potential of the electron reservoir.When the derivative is expressed in terms of the three-state ensemble model,in the regime of low temperatures up to temperatures of chemical interest,one finds that the thermodynamic dual descriptor can be expressed as?f_T(r)=(β/2)C[f^+(r)-f^-(r)],whereβ=1/k_BT,Cis a global quantity that depends on the temperature and global electronic properties of the molecule(the first ionization potential and the electron affinity),C=1 for systems with zero fractional charge,and C=C_ω>0(albeit very close to zero)for systems with nonzero fractional charge,,and f^+(r)and f^-(r)are the nucleophilic and electrophilic Fukui functions,respectively.The quantity within the square brackets is the original definition of the dual descriptor.As the local terms(the ones containing regioselectivity information)are equal to those of the dual descriptor,?f_T(r)has the same regioselectivity information,multiplied by the global quantity(β/2)C.This implies that the regioselectivity information contained in the original dual descriptor is preserved at all temperatures different from zero,and for any value of C>0.One of the most important features of this new definition is that it avoidsthe undesired Dirac delta behavior observed when the second order partial derivative of the average density is taken with respect to the average number of electrons,using the exact density depe

关键词： Dual descriptor Chemical stability Finite temperature chemical reactivity theory Fractional average number of electrons Amphiphilicity

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The Gboko Limestone, Yandev, Benue State, Nigeria: Geology, Geochemistry and Industrial Potentials

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Geomaterials 2017年第2期7卷 51-63页

作者： Anuba Basil Ofulume Sabinus Ikechukwu Ibeneme Donatus Maduka Orazulike Ibrahim vela Haruna Sani Aishatu Diugo Okechukwu Ikoro Stephen Ikpendu Nwankwo Nnaemeka Oluchukwu Ezetoha joseph Azi Bulus Department of Geology Federal University of Technology Owerri Nigeria GEM Executive Education Grenoble Ecole De Management Rue Pierre Semard Grenoble France Department of Geology Federal University of Technology Yola Nigeria Department of Geology University of Maiduguri Maiduguri Nigeria Department of Architecture Federal University of Technology Owerri Nigeria Department of Geology University of Jos Jos Nigeria

The Cretaceous shallow marine Gboko limestone, Yandev, Nigeria is a component of the sedimentary fill of the 800 km NE-SW trending Benue Trough, Nigeria. The limestone is made up of thin bedded to massive limestone beds interspersed with laminated grey shale having foraminifera as the dominant fossil. The limestone has both mud supported and grain supported texture, and micrites constitute about 75% of the limestone. Bulk chemical composition analysis of the limestone reveals average CaCO3 of 92.41% and a range of 77.50% - 99.00%. Mineralogical impurities include quartz, dolomite, pyrrhotite, fluorapatite etc. Trace elements concentration analysis was carried out using Energy Dispersive X-ray (EDXRF) spectrophotometry and showed the following trace elements: Mn (841.3 ppm), Sr (444.6 ppm), Fe (470 ppm), Zn (114.6 ppm) and Pb (116.4 ppm). Calcining the limestone in a laboratory muffle furnace at 1050°C for 90 minutes produced a compact, soft burnt porous and reactive lime that does not crumble into fines. The lime so produced neither meets the requirements of the Steel Making Shop (SMS) of the Ajaokuta Steel Plant nor could it be used in the growing sugar refining industry in Nigeria. It can however be used in the food and the food by-products industry, environmental, agricultural and petroleum industries etc. The raw stone remains a major source of raw materials for cement manufacture for the ever expanding building industry.

关键词： Benue Trough Calcination Fluxing Geochemistry Gboko Limestone

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