Proton speciation and microspeciation of vinpocetine and related compounds in aqueous and biomimetic media

Károly Mazák, András Nemes, B. Noszál

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Purpose. The determination of protonation macroconstants of twelve compounds in the vineamine drug family and the determination of protonation microconstants of cis- and trans-apovincaminic acid in media of various solvent composition to characterise their site-specific basicity and to estimate the concentration of the membrane-penetrating and receptor-binding forms. Methods. UV-pH litrations have been used to determine the protonation macroconstants in 10-43 wt% methanol/water mixtures. Yasuda-Shedlovsky extrapolation was applied to obtain aqueous logK values for compounds sparingly soluble in water. Protonation microconstants were also determined by deductive methods for compounds of free carboxylic group. Results. In the case of the two water-soluble compounds the extrapolated and the directly measured aqueous logK values were in good agreement, verifying all other extrapolated data. Compounds of cisD/E ring anellation are 0.4-0.8 logK units more basic than their epimeric, trans counterparts. The pH-dependent distribution of apovincaminic acid microspecies in aqueous and membrane-like media is depicted in microspeciation diagrams. Conclusions. The N(4) nitrogen is more shielded by the adjacent ethyl group in trans-D/E ring anellation eburnanes than in cis ones, as reflected by the protonation constants. Solvent-dependent basicity data predict superiority of trans isomers in lipophilicity and membrane-penetrating ability.

Original languageEnglish
Pages (from-to)1757-1763
Number of pages7
JournalPharmaceutical Research
Volume16
Issue number11
DOIs
Publication statusPublished - 1999

Fingerprint

vinpocetine
Biomimetics
Protonation
Protons
Membranes
Water
Alkalinity
Methanol
Nitrogen
Extrapolation
Isomers
Pharmaceutical Preparations

Keywords

  • Apovincaminic acid
  • Microspeciation
  • Protonation constants
  • Vincamine
  • Vinpocetine

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

Proton speciation and microspeciation of vinpocetine and related compounds in aqueous and biomimetic media. / Mazák, Károly; Nemes, András; Noszál, B.

In: Pharmaceutical Research, Vol. 16, No. 11, 1999, p. 1757-1763.

Research output: Contribution to journalArticle

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N2 - Purpose. The determination of protonation macroconstants of twelve compounds in the vineamine drug family and the determination of protonation microconstants of cis- and trans-apovincaminic acid in media of various solvent composition to characterise their site-specific basicity and to estimate the concentration of the membrane-penetrating and receptor-binding forms. Methods. UV-pH litrations have been used to determine the protonation macroconstants in 10-43 wt% methanol/water mixtures. Yasuda-Shedlovsky extrapolation was applied to obtain aqueous logK values for compounds sparingly soluble in water. Protonation microconstants were also determined by deductive methods for compounds of free carboxylic group. Results. In the case of the two water-soluble compounds the extrapolated and the directly measured aqueous logK values were in good agreement, verifying all other extrapolated data. Compounds of cisD/E ring anellation are 0.4-0.8 logK units more basic than their epimeric, trans counterparts. The pH-dependent distribution of apovincaminic acid microspecies in aqueous and membrane-like media is depicted in microspeciation diagrams. Conclusions. The N(4) nitrogen is more shielded by the adjacent ethyl group in trans-D/E ring anellation eburnanes than in cis ones, as reflected by the protonation constants. Solvent-dependent basicity data predict superiority of trans isomers in lipophilicity and membrane-penetrating ability.

AB - Purpose. The determination of protonation macroconstants of twelve compounds in the vineamine drug family and the determination of protonation microconstants of cis- and trans-apovincaminic acid in media of various solvent composition to characterise their site-specific basicity and to estimate the concentration of the membrane-penetrating and receptor-binding forms. Methods. UV-pH litrations have been used to determine the protonation macroconstants in 10-43 wt% methanol/water mixtures. Yasuda-Shedlovsky extrapolation was applied to obtain aqueous logK values for compounds sparingly soluble in water. Protonation microconstants were also determined by deductive methods for compounds of free carboxylic group. Results. In the case of the two water-soluble compounds the extrapolated and the directly measured aqueous logK values were in good agreement, verifying all other extrapolated data. Compounds of cisD/E ring anellation are 0.4-0.8 logK units more basic than their epimeric, trans counterparts. The pH-dependent distribution of apovincaminic acid microspecies in aqueous and membrane-like media is depicted in microspeciation diagrams. Conclusions. The N(4) nitrogen is more shielded by the adjacent ethyl group in trans-D/E ring anellation eburnanes than in cis ones, as reflected by the protonation constants. Solvent-dependent basicity data predict superiority of trans isomers in lipophilicity and membrane-penetrating ability.

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