neurotoxicity and mechanisms of induced hyperexcitability

EXPERIMENTALMass spectrometry (MS)Dextromethorphan drug (DMP)Figure 1. Structure and numbering system of DMP for, C, N and O skelton.may be deduced, thus greatly facilitating the interpretation ofthermal degradation processes. In contrast, the computationalquantum chemistry could provide additional informationabout the atoms and bonds, which could be used successfullyin an interpretation of experimental results [23]. The applicationof the computational quantum chemistry in addition toexperimental results (MS and TA) gives valuable informationabout the atoms and bonds, which helps in the descriptionand prediction of the primary fragmentation site of cleavageand subsequent ones [24-28].Although the literature is wealthy in information relatedto the biological activities of DMP and its metabolites in vivoand in vitro [3-6], there seems to be a lack of any correlationbetween chemical behaviour and its electronic structure.The main aim of this work was to perform an experimentaland theoretical investigation of DM using thermalanalyses (TA) and EI mass spectral (MS) fragmentation at70 eV. In addition, MO calculations were performed usingthe PM3 procedure on the neutral molecule and chargedmolecule to investigate geometrical parameters (bondlength, bond order, bond strain, heats of formation ionisationenergy) and charge distribution.The calculations correlated the experimental results[TA and MS] to obtained information regarding the stabilityof the drug and the prediction of the site of primaryfragmentation and subsequent ones. This study could behelpful in establishing a quantitative and qualitative structure–activityrelationship for the drug, which is the mainobjective of this work. It is worth mentioning that there isscant literature concerning such a comparative study.Moreover, the authors tried to correlate and discuss thestructure reactivity and relationship between DM and Codeine[26], which are chemically related to each other [2]and which affect the O and OH on MS and TA and MOparameters. In addition, they attempted to find the metabolitestructures in the mass spectrum and correlated thebiological behaviour of the two drugs.The electron ionisation (EI) mass spectrum of DMPwas obtained using a Shimadzu GC-MS-Qp 1000 PX quadruplemass spectrometer with an electron multiplier detectorequipped with the GC-MS data system. The directprobe for solid material was used in this study. The samplewas put into a glass sample micro vial by a needle (˜ 1 μgmax). The vial was installed on the tip of the DP containingthe heating cable and was inserted into the evacuatedion source. The sample was ionised by an electron beamemitted from the filament with the generated ions beingeffectively introduced into the analyser by the focusing andextractor lens systems. The MS was continuously scanned,and the spectra obtained were stored. The electron ionisationmass spectra were obtained at an ionising energyvalue of 70 eV, ionisation current of 60 μA and a vacuumgreater than 10 -6 tor r.Thermal analysis (TA)The thermal analyses of DMP were made using a conventionalthermal analyser (Shimadzu system of DTA-50and 30 series TG-50). The mass loss for 5 mg of sample andthe heat response to changes in the sample were measuredfrom room temperature up to 600ºC. The heating rate in aninert argon atmosphere was 10ºC min -1 . These instrumentswere calibrated using indium metal as a thermal stable material.The reproducibility of the instrument reading was determinedby repeating each experiment more than twice.Quantum chemical calculationsThe MO calculations were performed using a semiempiricalmolecular orbital calculation. The method usedin these computations was the parametric PM-3 methoddescribed by Stewart [29]. The geometry of all stable speciesstudied was completely optimised with respect to allgeometrical variables using the Eigen vector following (EF)routine [30]. The program was run under the molecularorbital calculation package MOPAC2000 by Stewart [31]for microcomputers.RESULTS AND DISCUSSIONThe chemistry and reactivity of pharmaceutical drugsare of great interest because of their importance in treatingvarious diseases. Knowledge of the thermal decompositionmechanism of the drug is very important to understandthe chemical processes in biological systems. It is difficultto establish the exact major fragmentation pathway in EIusing conventional MS. However, the combination of experimentaltechniques (TA and MS) and MO calculation isvery important to understand the following topics:22