Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

Mazák, Károly; Noszál, Béla

doi:10.1016/j.jpba.2016.03.053

Cited by 34 publications

(30 citation statements)

References 100 publications

(146 reference statements)

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“…Moreover, the site‐specific acid‐base properties for molecules with several protonation sites, characterize even the localization of charges within the molecule, which is especially important for passive membrane transport . Consideration of acid‐base properties together with other molecular properties is essential in drug discovery, as pharmacodynamically active drug candidate molecules with unfavourable pharmacokinetic properties cannot even reach the intended target molecule . Highly basic compounds are unsuitable for acting in the CNS as they are liable to be substrates of the active efflux transporter P‐glycoprotein (P‐gp, or MDR1) .…”

Section: Acid‐base Propertiesmentioning

confidence: 99%

“…The protonation scheme of naloxone is depicted in Figure , showing the two different protonation isomers of the monoprotonated, neutral form as well. Figure also shows the microscopic protonation constants (microconstants) that quantify the basicity of individual protonation sites, when the protonation states of all other sites are definite in the molecule . Indices N and O denote the nitrogen atom in the amino group and the oxygen atom in the phenolate group, respectively.…”

Section: Acid‐base Propertiesmentioning

confidence: 99%

“…In the knowledge of the pH of the environment and the macro‐ and microconstants the pH‐dependent distribution of macro‐and microspecies can be calculated. Microspeciation has shown that it is not necessarily the major species that is reactive in biochemical processes …”

Section: Acid‐base Propertiesmentioning

confidence: 99%

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Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

2019

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This review focuses on recent developments in the physicochemical profiling of morphine and other opioids. The acid‐base properties and lipophilicity of these compounds is discussed at the microscopic, species‐specific level. Examples are provided where this type of information can reveal the mechanism of pharmacokinetic processes at the submolecular level. The role of lipophilicity in quantitative structure–activity relationship (QSAR) studies of opioids is reviewed. The physicochemical properties and pharmacology of the main metabolites of morphine are also discussed. Recent studies indicate that the active metabolite morphine‐6‐glucuronide (M6G) can contribute to the analgesic activity of systemically administered morphine. The unexpectedly high lipophilicity of M6G partly accounts for its analgesic activity. When administered parenterally, another suspected minor metabolite, morphine‐6‐sulfate (M6S) has superior antinociceptive effects to those of morphine. However, because sulfate esters of morphine derivatives cannot cross the blood‐brain barrier these esters may be good candidates to develop peripheral analgesic drugs.

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Section: Acid‐base Propertiesmentioning

confidence: 99%

Section: Acid‐base Propertiesmentioning

confidence: 99%

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Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

2019

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“…These coexisting species produce composite analytical signals, but act individually in specific biochemical processes. The physicochemical parameters and analytical concentrations of these microspecies can only be obtained by microspeciation, a composite, indirect methodology that uses at least two experimental techniques, and/or auxiliary compounds, followed by an appropriate evaluation method …”

Section: Introductionmentioning

confidence: 99%

“…The physicochemical parameters and analytical concentrations of these microspecies can only be obtained by microspeciation, a composite, indirect methodology that uses at least two experimental techniques, and/or auxiliary compounds, followed by an appropriate evaluation method. [6] The protonation scheme of serotonin is depicted in Fig. 1.…”

Section: Introductionmentioning

confidence: 99%

Passive Membrane Penetration of the Serotonin Precursor 5‐Hydroxytryptophan is Controlled by Its Zwitterion

Mazák

Noszál

2017

Chemistry & Biodiversity

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Species-specific partition coefficients in the octanol/water system were determined for the neurotransmitter serotonin (5-HT) and its precursor 5-hydroxytryptophan (5-HTP). The pH-independent partition coefficients (p) of the individual microspecies were determined by combination of experimentally measured distribution constants and a custom-tailored evaluation method, using highly similar auxiliary compounds. Experimental microscopic partition coefficients for triprotic molecules have only been reported before for thyroxine and its derivatives. The parabolic pH-distribution profile of 5-HT shows the dominance of the lipophilic non-charged microspecies, with a log p of 0.66. However, the most lipophilic non-charged form of 5-HTP, with a log p of 0.31, has no significant contribution to the distribution coefficient at any pH value. Instead, the less lipophilic zwitterionic protonation isomer dominates the distribution in the pH range 2.10 - 11.11. Although the non-charged microspecies of 5-HTP is 151 times more lipophilic than its zwitterionic protonation isomer, the overwhelming dominance of the zwitterionic form ensures that its contribution to the overall lipophilicity exceeds 1320 times that of the non-charged one. This fact is another counter-example of the widespread belief that passive diffusion into lipophilic media is predominated by the non-charged species. The lipophilicity profile of 5-HT and 5-HTP is depicted in terms of species-specific lipophilicities.

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Synthesis of 3‐O‐Carboxyalkyl Morphine Derivatives and Characterization of Their Acid‐Base Properties

Köteles

Mazák

Tóth

et al. 2021

Chemistry & Biodiversity

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The C-3 phenolic hydroxy group containing morphine derivatives (morphine, oxymorphone, naloxone, naltrexone) are excellent candidates for the synthesis of 3-O-functionalized molecules. Achieving free carboxylic group containing derivatives gives the opportunity for further modification and conjugation that could be used for immunization and immunoassays. For this purpose ethyl bromo-and chloroacetate can be used as O-alkylating agents. Hydrolyzing the products affords the appropriate free carboxylic group containing 3-O-carboxyalkyl derivatives. As these molecules contain an acidic and a basic functional group the protonation macro-and microconstants were determined too, using pH-potentiometry and NMR-pH titration, beside fully characterizing their structure using IR, CD, NMR and HR-MS measurements.

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Advances in microspeciation of drugs and biomolecules: Species-specific concentrations, acid-base properties and related parameters

Cited by 34 publications

References 100 publications

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

Advances in the Physicochemical Profiling of Opioid Compounds of Therapeutic Interest

Passive Membrane Penetration of the Serotonin Precursor 5‐Hydroxytryptophan is Controlled by Its Zwitterion

Synthesis of 3‐O‐Carboxyalkyl Morphine Derivatives and Characterization of Their Acid‐Base Properties

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