A thermodynamic analysis of solvation effects on the basicities of alkylamines. An electrostatic analysis of substituent effects

Aue, Donald H.; Webb, Hugh M.; Bowers, Michael T.

doi:10.1021/ja00418a002

Cited by 249 publications

(135 citation statements)

References 3 publications

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“…In fact, according to previous data Talon et al, 2001), To5 showed a higher pK a than Toc, and the homologating of the amino group by one methylene further increases the basicity. As generally observed for tertiary amines compared with secondary amines in an aqueous environment (Aue et al, 1972), Benzyl-To5 and Benzyl-To9 were less basic than the respective nonbenzylated analogs. No linear correlation was found between pK a and drug affinities for either resting or inactivated channels, so we focused on the relationship between pK a and use-dependent behavior.…”

supporting

confidence: 64%

Optimal Requirements for High Affinity and Use-Dependent Block of Skeletal Muscle Sodium Channel by N-Benzyl Analogs of Tocainide-Like Compounds

Talon²,

Bellis³

et al. 2003

Mol Pharmacol

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Newly synthesized tocainide analogs were tested for their state-dependent affinity and use-dependent behavior on sodium currents (I Na ) of adult skeletal muscle fibers by means of the Vaseline-gap voltage clamp method. The drugs had the pharmacophore amino group constrained in position ␣ [N-(2,6-dimethylphenyl)pyrrolidine-2-carboxamide (To5)] or ␤ [N-(2,6-dimethylphenyl)pyrrolidine-3-carboxamide (To9)] in a prolinelike cycle and/or linked to a lipophilic benzyl moiety as in N-benzyl-tocainide (Benzyl-Toc), 1-benzyl-To5 (Benzyl-To5), and 1-benzyl-To9 (Benzyl-To9). I Na were elicited with pulses to Ϫ20 mV from different holding potentials (Ϫ140, Ϫ100, and Ϫ70 mV) and stimulation frequencies (2 and 10 Hz). All compounds were voltage-dependent and use-dependent channel blockers. The presence of a proline-like cycle increased the potency; i.e., To5 was 3-and 10-fold more effective than Toc in blocking I Na at the holding potential of Ϫ140 and Ϫ70 mV, respectively. The benzyl group on the amine further enhanced drug effectiveness with the following scale: Benzyl-To9 Ն Benzyl-Toc Ͼ Benzyl-To5. At a holding potential of Ϫ100 mV and 10-Hz stimulation, Benzyl-To9 blocked I Na with a half-maximal concentration of 0.5 M, being 60 and 400 times more potent than To9 and Toc, respectively. The similar effectiveness of Benzyl-Toc and Benzyl-To9 was paralleled by a similar spatial arrangement by equilibrium geometry modeling. In addition, the latter had a higher pK a value that probably contributed to a slow kinetic during its high use-dependent behavior. Benzyl-To5 had its lowest energy level at a more folded conformation that justifies the less favorable profile among the N-benzylated analogs. The new compounds are the most potent tocainide-like sodium channel blockers so far described and have high therapeutic potentials.The block of voltage-gated Na ϩ channel by local anestheticlike (LA) drugs has therapeutic value for numerous disorders characterized by abnormal membrane excitability (Clare et al., 2000). Different channel types show different sensitivities to LAs; however, the structural basis for this difference is still poorly understood (Wang et al., 1996;Li et al., 1999;2002). The selective activity on tissue displaying abnormal excitability pattern is based on the state-dependence of LA effect (i.e., a stronger potency at depolarized membrane potential or during high frequency trains of channel activity) (Catterall, 2002). This effect is related to drug interaction with a receptor whose affinity for ligands changes with the state-dependent transitions of the channel, the affinity being the highest when the channels open or inactivate. Mutagenesis studies identified various amino acid residues, localized in the S6 segments of each homologous domain of the ␣ subunit, as critical for LA binding and activity on Na ϩ channels of various excitable tissues (Ragsdale et al., 1994(Ragsdale et al., , 1996Wright et al., 1998;Li et al., 1999;Nau et al., 1999;Wang et al., 2000;Yarov-Yarovoy et al., 2001, 2002. LAs may int...

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supporting

confidence: 64%

Optimal Requirements for High Affinity and Use-Dependent Block of Skeletal Muscle Sodium Channel by N-Benzyl Analogs of Tocainide-Like Compounds

Talon²,

Bellis³

et al. 2003

Mol Pharmacol

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“…Solvation free energies are not directly available from experiments. However, measurements of DH solv [49][50][51] and an estimation of TDS [52] have allowed an experimental evaluation of DG solv . [53] Our calculated values of DG solv agree well for TMA ).…”

Section: Computational Detailsmentioning

confidence: 99%

Amphiphilic Organic Ion Pairs in Solution: A Theoretical Study

2007

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The macroscopic manifestation of hydrophobic interactions for amphiphilic organic ion pairs (tetraalkylammonium-anion) has been shown experimentally by measuring their association constants and their affinity with the organic phase. Beyond a certain size, there is a direct relation between association constants and chain lengths in tetraalkylammonium ions. We propose to cast a bridge between these results and geometrical properties considered at the level of a single ion pair by means of quantum chemistry calculations performed on model systems: trimethylalkylammonium-pentyl sulfate instead of tetraalkylammonium-dodecyl sulfate. Two limiting cases are considered: head-to-head configurations, which yield an optimal electrostatic interaction between polar heads, and parallel configurations with a balance between electrostatic and hydrophobic interactions. All properties (geometries, complexation energies, and atomic charges) were obtained at the MP2 level of calculation, with water described by a continuum model (CPCM). Dispersion forces link hydrocarbon chains of tetraalkylammonium ions and pentyl sulfate, thus yielding (for the largest ion pairs) parallel configurations favored with respect to head-to-head geometries by solute-solvent electrostatic interactions. Given the small experimental association energies, we probe the accuracy limit of the MP2 and CPCM methods. However, clear trends are obtained as a function of chain length, which agree with the experimental observations. The calculated monotonic stabilization of ion pairs when the hydrocarbon chain increases in length is discussed in terms of electrostatic interactions (between ions and between ion pairs and water), dispersion forces, and cavitation energies.

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“…Table 1 and Table 2). We tried to correlate the MINDO/3 polarization energies with experimental proton affinities [14,15] (see Fig. 3 a and Figure 3 b).…”

Section: Resultsmentioning

confidence: 99%

Quantumchemical Calculations on Nitrogen Bases. Part 6 *: Analysis of the Proton Affinities of Aliphatic Amines Using the Kitaura-Morokuma Scheme and the MINDO/3 Method

Raabe

Fleischhauer

1987

Zeitschrift Für Naturforschung A

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The energy partitioning scheme of Morokuma et al. has been applied to the proton affinities of fourteen aliphatic amines. The electrostatic, the polarization and the charge transfer component of the proton affinities have been calculated using the MINDO/3 method. Two different sets of structural parameters have been used for the complexes of the bases and the attacking proton. Within the framework of the semiempirical method employed here, the electrostatic interaction between an attacking proton and the base was found to be positive as a result of the relative magnitudes of the repulsion terms used in the proton-electron and the proton-core interactions.In the case of the polarization term our findings roughly parallel those of Morokuma. For one of the two sets of structural parameters a good and almost group overlapping correlation was found between polarization energies and experimental proton affinities: the polarization part was found to decrease with increasing proton affinity. Independent of the choice of the amine geometries, the results for the charge transfer energy contradict the nonempirical data of Morokuma: Contrarily to his results we found values which increase in the order ammonia < methylamine < dimethylamine < trimethylamine.

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A thermodynamic analysis of solvation effects on the basicities of alkylamines. An electrostatic analysis of substituent effects

Cited by 249 publications

References 3 publications

Optimal Requirements for High Affinity and Use-Dependent Block of Skeletal Muscle Sodium Channel by N-Benzyl Analogs of Tocainide-Like Compounds

Optimal Requirements for High Affinity and Use-Dependent Block of Skeletal Muscle Sodium Channel by N-Benzyl Analogs of Tocainide-Like Compounds

Amphiphilic Organic Ion Pairs in Solution: A Theoretical Study

Quantumchemical Calculations on Nitrogen Bases. Part 6 *: Analysis of the Proton Affinities of Aliphatic Amines Using the Kitaura-Morokuma Scheme and the MINDO/3 Method

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