DFT study of species derived from the narcotic antagonist naloxone

Abstract

The functional hybrid B3LYP and the 6-31G* basis set have been employed to study the theoretical structures of free base, cationic and hydrochloride species of naloxone in gas phase and in aqueous solution. The SCRF methodology and the PCM method were used to optimize the species in solution while the solvation energies were computed with the universal solvation model. The harmonic force fields of three species in the two media were computed with the SQMFF methodology and the Molvib program while the complete vibrational assignments of bands observed in the experimental available ATR and Raman spectra were performed by using the harmonic force fields and the normal internal coordinates. Therefore, the expected 129, 132 and 135 vibration normal modes for the free base, cationic and hydrochloride species of naloxone, respectively are here reported. The free base of naloxone evidence the higher solvation energy value, as compared with those reported for S(-)-promethazine, R(+)-promethazine, cyclizine, morphine, cocaine, scopolamine, heroin, and tropane alkaloids. The cationic species shows a solvation energy value (-302.45 kJ/mol) closer to observed for morphine (-309.19 kJ/mol) while the value for the hydrochloride species (-122.28 kJ/mol) is near to scopolamine value (-122.74 kJ/mol). AIM analyses show ionic characteristic of N-HCl bonds in the hydrochloride species and suggest that this species in both media is as cationic one, as supported by the positive MK charges on the N5 atoms in the hydrochloride species in both media and by the absence in the ATR spectrum of band at 2405 cm-1, associated to N5-H46 stretching mode. Moreover, frontier orbitals studies evidence that the allyl chains present in the three species of naloxone diminishing the gap values increasing their reactivities, as compared with the other species containing the N-CH3 group. The f(N-H) force constants for the hydrochloride species is lower than the corresponding in solution, a result also observed for morphine (2.73 and 4.61 mdyn Å-1), cocaine (3.23 and 4.79 mdyn Å-1) and tropane (2.70 and 4.69 mdyn Å-1) alkaloids. Comparisons between experimental infrared, Raman and ultraviolet-visible spectra with the corresponding predicted show good correlations.

Correlations in hydrochloride drugs with diverse pharmacological activities. Role of N-H…Cl bonds

“…Previous vibrational studies on hydrochloride/hydrobromide species have showed that the strong IR bands assigned to the N-H stretching modes are predicted between 2700 and 1500 cm -1 by using B3LYP/6-31G* calculations and, that they are not present in the corresponding experimental spectra because the species are present in the solid state and in aqueous solution as cationic ones [11][12][13][15][16][17][18][19][20][21][22][23][24]. Then, the presence of Cl atom in the hydrochloride species shift the N-H stretching modes toward lower wavenumbers, as compared with the observed for the cationic species (3350 and 3150 cm -1 ).…”

“…Previous structural and vibrational studies on hydrochloride/hydrobromide species with different biological activities have evidenced that the intense IR bands predicted between 2700 and 1500 cm -1 for all hydrochloride species and attributed to N-H stretching modes of N-HCl bonds, are not present in the corresponding experimental spectra. This way, the combination of DFT calculations with the experimental infrared and Raman spectra and the scaled quantum mechanical force field (SQMFF) methodology, have evidenced that these species are as cationic ones in the solid state and, obviously, also in aqueous solution [11][12][13][15][16][17][18][19][20][21][22][23][24]. Hence, it is essential to investigate the role of N-HCl bonds in hydrochloride drugs with different pharmacological properties because, so far, there are no studies on the influence of those bonds on their properties, in relation to the important biological properties that they present.…”

“…Moreover, from that point of view, it is interesting to know the properties of different hydrochloride forms to evaluate if these species are better as drugs than the hydrobromide ones. Taking into account that in the literature there are a large number of hydrochloride species with many applications, in this study, only ten alkaloids, including a psychotropic species, three antihistaminic and three antihypertensive agents were considered because their properties were in general already published [6][7][8][11][12][13][14][15][16][17][18][19][20][21][22][23][24].…”

“…Thus, in this work, the hydrochloride species of tropane, gramine, morphine, cocaine, methadone, naloxone, heroin and scopolamine and, also as scopolamine hydrobromide alkaloids with the psychotropic 2-CB agent, the hydrochloride species of tolazoline, clonidine and guanfacine antihypertensive agents and, the hydrochloride species of diphenhydramine, cyclizine and promethazine antihistaminic agents were studied [6][7][8][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Here, to know the differences between the properties of the hydrochloride form of scopolamine the hydrobromide form is also studied [17].…”

“…Tertiary N atoms that contain the N-HCl bonds of the hydrochloride or hydrobromide species are linked to one or two N-CH 3 groups and, also to rings, as in the alkaloids but, naloxone is the only species linked to two N-CH 3 groups and to an allyl >N-CH 2 -CH=CH 2 group. But, in the species of naloxone the N-HCl bond is not linked to a ring, as gramine, methadone, clonidine, guanfacine, tolazoline diphenhydramine and promethazine [6][7][8][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. However, the hydrochloride form of 2-CB is the only species where the N-HCl bond belong to a NH 2 group instead of N-CH 3 group [20].…”