Apparent Lipophilicity Research Articles

Lipophilic Salts and Lipid-Based Formulations: Enhancing the Oral Delivery of Octreotide.

Successful oral peptide delivery faces two major hurdles: low enzymatic stability in the gastro-intestinal lumen and poor intestinal membrane permeability. While lipid-based formulations (LBF) have the potential to overcome these barriers, effective formulation of peptides remains challenging. Lipophilic salt (LS) technology can increase the apparent lipophilicity of peptides, making them more suitable for LBF. As a model therapeutic peptide, octreotide (OCT) was converted to thedocusate LS (OCT.DoS2), and compared to the commercial acetate salt (OCT.OAc2) in oral absorption studies and related in vitro studies, including parallel artificial membrane permeability assay (PAMPA), Caco-2, in situ intestine perfusion, and simulated digestion in vitro models. The in vivo oral absorption of OCT.DoS2 and OCT.OAc2 formulated in self-emulsifying drug delivery systems (SEDDS) was studied in rats. LS formulation improved thesolubility and loading of OCT in LBF excipients and OCT.DoS2 in combination with SEDDS showed higher OCT absorption than the acetate comparator in the in vivo studies in rats. The Caco-2 and in situ intestine perfusion models indicated no increases in permeability for OCT.DoS2. However, the in vitro digestion studies showed reduced enzymatic degradation of OCT.DoS2 when formulated in the SEDDS formulations. Further in vitro dissociation and release studies suggest that the enhanced bioavailability of OCT from SEDDS-incorporating OCT.DoS2 is likely a result of higher partitioning into and prolonged retention within lipid colloid structures. The combination of LS and LBF enhanced the in vivo oral absorption of OCT primarily via the protective effect of LBF sheltering the peptide from gastrointestinal degradation.

Intramolecular hydrogen bonding to improve membrane permeability and absorption in beyond rule of five chemical space

Utilising ‘beyond rule of five’ chemical space is becoming increasingly important in drug design, but is usually at odds with good oral absorption. The formation of intramolecular hydrogen bonds in drug molecules is hypothesised to shield polarity facilitating improved membrane permeability and intestinal absorption. NMR based evidence for intramolecular hydrogen bonding in several ‘beyond rule of five’ oral drugs is described. Furthermore, the propensity for these drugs to form intramolecular hydrogen bonds could be predicted for through modelling the lowest energy conformation in the gas phase. The modulation of apparent lipophilicity through intramolecular hydrogen bonding in these molecules is supported by intrinsic cell permeability and intestinal absorption data in rat and human.

In silico Prediction of Human Oral Absorption Based on QSAR Analyses of PAMPA Permeability

The parallel artificial membrane permeation assay (PAMPA) was developed as a model for the prediction of transcellular permeation in the process of drug absorption. Our research group has measured the PAMPA permeability of peptide-related compounds, diverse drugs, and agrochemicals. This work led to a classical quantitative structure-activity relationship (QSAR) equation for PAMPA permeability coefficients of structurally diverse compounds based on simple physicochemical parameters such as lipophilicity at a particular pH (log P(oct) and |pKa-pH|), H-bond acceptor ability (SA(HA)), and H-bond donor ability (SA(HD)). Since the PAMPA permeability of lipophilic compounds decreased with their apparent lipophilicity due to the unstirred water layer (UWL) barrier on membrane surfaces and to membrane retention, a bilinear QSAR model was introduced to explain the permeability of a broader set of compounds using the same physicochemical parameters as those used for the linear model. We also compared PAMPA and Caco-2 cell permeability coefficients of compounds transported by various absorption mechanisms. The compounds were classified according to their absorption pathway (passively transported compounds, actively transported compounds, and compounds excreted by efflux systems) in the plot of Caco-2 vs. PAMPA permeability. Finally, based on the QSAR analyses of PAMPA permeability, an in silico prediction model of human oral absorption for possibly transported compounds was proposed, and the usefulness of the model was examined.

Imidazole H3-antagonists: relationship between structure and ex vivo binding to rat brain H3-receptors.

H3-antagonists possess promising pharmacological effects on awakening, learning and memory, but few data on their access to the central nervous system (CNS) have been reported so far. The purpose of this work was to investigate the relationships between structure and brain penetration of a series of H3-antagonists, using ex vivo binding experiments in rats. H3-antagonists belonging to different chemical classes but all having an imidazole ring, an alkyl spacer, a polar fragment and a lipophilic ending group, were selected among the numerous H3-antagonists recently described by us. Ex vivo binding studies were performed by inhibiting specific [3H]-(R)-alpha-methylhistamine ([3H]-RAMHA) binding to rat cerebral cortical membranes following H3-antagonist peripheral administration. Ionization constants and partition coefficients in n-octanol/water and 1,2-dichloroethane/water were determined by the potentiometric pH-metric method and were compared to the ex vivo binding potencies to analyse structure-property relationships (SPR). In the ex vivo assay, the H3-antagonists showed different potencies (pED50) not correlated to their in vitro H3-receptor binding affinities (pKi). Compound 4a, having a benzothiazol-2-yl-thioethyl chain, showed high ex vivo potency (ED50=1.35 mg kg(-1) i.p.) and a fast brain penetration, eliciting maximal displacement of [3H]-RAMHA already 5 min after i.v. or i.p. administration. Ex vivo binding assays of three compounds, following i.v. and i.p. administration, showed that the observed i.p. ex vivo potencies were not significantly affected by biotransformation. Within the set of compounds, those having a better ability to reach the CNS had a logDoct(7.4) in the range 2-3.5, and a DeltalogPoct-dce < 2. The combined use of two easily measurable physicochemical descriptors, namely logDoct(7.4) (apparent lipophilicity at pH 7.4) and DeltalogPoct-dce (a descriptor of H-bond donor capacity) allowed to model brain permeation of the majority of the compounds examined.

Discovery of a thieno[2,3-d]pyrimidine-2,4-dione bearing a p-methoxyureidophenyl moiety at the 6-position: a highly potent and orally bioavailable non-peptide antagonist for the human luteinizing hormone-releasing hormone receptor.

We have previously disclosed the first potent and orally effective non-peptide antagonist for the human luteinizing hormone-releasing hormone (LHRH) receptor, a thieno[2,3-b]pyridin-4-one derivative, T-98475 (1). Extensive research on developing non-peptide LHRH antagonists has been carried out by employing a strategy of replacing the thienopyridin-4-one nucleus with other heterocyclic surrogates. We describe herein the design and synthesis of a series of thieno[2,3-d]pyrimidine-2,4-dione derivatives containing a biaryl moiety, which led to the discovery of a highly potent and orally active non-peptide LHRH antagonist, 5-(N-benzyl-N-methylaminomethyl)-1-(2,6-difluorobenzyl)-6-[4-(3-methoxyureido)phenyl]-3-phenylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (9k: TAK-013). Compound 9k showed high binding affinity and potent in vitro antagonistic activity for the human receptor with half-maximal inhibition concentration (IC(50)) values of 0.1 and 0.06 nM, respectively. Oral administration of 9k caused almost complete suppression of the plasma LH levels in castrated male cynomolgus monkeys at a 30 mg/kg dose with sufficient duration of action (more than 24 h). The results demonstrated that the thienopyrimidine-2,4-dione core is an excellent surrogate for the thienopyridin-4-one and that thienopyrimidine-2,4-diones and thienopyridin-4-ones constitute a new class of potent and orally bioavailable LHRH receptor antagonists. Furthermore, molecular modeling studies indicate that the unique methoxyurea side chain of 9k preferentially forms an intramolecular hydrogen bond between the aniline NH and the methoxy oxygen atom. The hydrogen bond will shield the hydrogen bonding moieties from the solvent and reduce the desolvation energy cost. It is therefore speculated that the intramolecular hydrogen bond resulting from judicious incorporation of an oxygen atom into the terminal alkyl group of the urea may increase the apparent lipophilicity to allow increased membrane permeability and consequently to improve the oral absorption of 9k in monkeys. On the basis of its profile, compound 9k has been selected as a candidate for clinical trials and it is expected that it will provide a new class of potential therapeutic agents for the clinical treatment of a variety of sex-hormone-dependent diseases.

Multivariate statistics of disposition pharmacokinetic parameters for structurally unrelated drugs used in therapeutics.

To explore the quantitative structure pharmacokinetic relationships of the disposition parameters: clearance (CL), apparent volume of drug distribution (V(ap)), fractal clearance (CL(f)), and fractal volume (v(f)) for 272 structurally unrelated drugs used in therapeutics. Literature data were used for CL and V(ap) whereas CL(f) and v(f) were estimated as described previously (Pharm. Res. 18, 1056, 2001 and 19, 697, 2002). A variety of molecular descriptors expressing lipophilicity, ionization, molecular size and hydrogen bonding capacity were estimated using computer packages. The data were analyzed using multivariate statistics. For each disposition parameter (CL, V(ap) CL(f), v(f)) PCA (principal component analysis) and PLS (projection to latent structures) were applied to the total set of data as well as to subsets of data. Drugs were divided into two classes (I and II) according to their v(f)/V(ap) ratio. Class I comprises 131 drugs with v(f)/V(ap) > 1, whereas class 11141 drugs with v(f)/V(ap) < 1. After initial PLS analysis, class I was subdivided in subclusters I(a) (30 drugs) and I(b) (101 drugs). It was found that I(a) included mostly acidic drugs with high protein binding, whereas class II comprises mainly basic, lipophilic compounds. No correlation was found between CL, V(ap), CL(f) and the used descriptors. Adequate PLS models were derived for v(f) considering subclusters I(a), I(b) and class II separately. The low v(f) values of class I(a) drugs were affected negatively from molecular size descriptors and non-polar surface area. For class I(b) drugs with intermediate v(f) values, apparent lipophilicity contributed positively, although molecular size descriptors and polarity were inhibitory factors. The high v(f) values of class II drugs were positively dependent on intrinsic lipophilicity and increased basicity, whereas polarity entered with negative contribution. The parameters V(ap), CL, and CL(f) fail to reflect the physicochemical properties of drugs. The transformation of V(ap) values to v(f) is the underlying cause for the valid models for v(f). These models allow a global consideration of molecular properties (lipophilicity, ionization, molecular size, polar surface area) which govern the distribution of drugs in the human body. The present study provides additional evidence for the physiologically sound concept of v(f).

Contribution of ion pair complexation with bile salts to biliary excretion of organic cations in rats.

The objective of this study was to examine whether ion pair complexation with endogenous bile salts in hepatocytes contributes to the preferential biliary excretion of organic cations (OCs). Tributylmethylammonium (TBuMA; mol wt 200) and triethylmethylammonium (TEMA; mol wt 116) were selected as model OCs that exhibit significant and negligible biliary excretion, respectively, in rats. The apparent lipophilicity of TBuMA, but not that of TEMA, was increased by the presence of either rat bile or specific bile salts, suggesting the formation of lipophilic ion pair complexes for TBuMA with bile salts in the liver. The uptake of TBuMA into canalicular liver plasma membrane (cLPM) vesicles, but not that of TEMA, was increased in the presence of bile salts, with a significant increase for both ATP-dependent transport and passive diffusion. The uptake of TBuMA in the presence of the bile salts was inhibited by representative P-glycoprotein (P-gp) substrates and vice versa, suggesting the involvement of P-gp in the canalicular excretion of TBuMA-bile salt complexes in vivo. Increased affinity toward P-gp is suggested as the mechanism responsible for the increased ATP-dependent transport for the ion pair complexes. We propose that ion pair formation with bile slats in hepatocytes may be responsible for the preferential biliary excretion of high-molecular-weight OCs including TBuMA.

Utilization of an intramolecular hydrogen bond to increase the CNS penetration of an NK(1) receptor antagonist.

This paper describes the synthesis and physical and biological effects of introducing different substituents at the alpha-position of the tryptophan containing neurokinin-1 receptor antagonist [(R)-2-(1H-indol-3-yl)-1-methyl-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (CI 1021). The described compounds all exhibit less than 5 nM binding affinities for the human neurokinin-1 receptor and selectivity over the tachykinin NK(2) and NK(3) receptor subtypes. Application of variable temperature nuclear magnetic resonance spectroscopy studies of the amide and urethane protons was utilized to determine the existence of an intramolecular hydrogen bond. This intramolecular hydrogen bond increases the apparent lipophilicity to allow increased central nervous system penetration and pharmacological activity (gerbil foot tap test) in the case of the highest affinity compound [(S)-1-dimethylaminomethyl-2-(1H-indol-3-yl)-1-((S)-1-phenyl-ethylcarbamoyl)-ethyl]-carbamic acid benzofuran-2-ylmethyl ester (PD 174424) over those analogues that could not form an intramolecular hydrogen bond.

The apparent lipophilicity of quaternary ammonium ions is influenced by galvani potential difference, not ion-pairing: a cyclic voltammetry study.

This work examines whether ion-pairing contributes to the apparent lipophilicity of cations, which is seen by a shake-flask or titrimetic method to be influenced by the nature and concentration of counter-ions. To solve this problem, the lipophilicity of several quaternary ammonium drugs was measured by cyclic voltammetry in the 1,2-dichloroethane/water system. The standard ionic partition coefficient values so obtained (log Pdce(o,C)) were correlated with log Poct values calculated by the CLOGP algorithm for the respective neutral molecules. The standard (i.e., intrinsic) lipophilicity values are shown to depend on a, the structure of the ion (nature, volume, charge), and b, on the Galvani potential difference at the ITIES (interface between two immiscible electrolyte solutions). The standard lipophilicity values were not influenced by counter-ions. In contrast, simulations showed that the increased apparent lipophilicity of cations, as measured by the shake-flask method in the presence of lipophilic anions, is fully accounted for by the resulting increase in the Galvani potential difference.

TLC-FTIR OF COLOR PIGMENTS OF CHESTNUT SAWDUST

The separation of color pigments of chestnut sawdust was carried out on various direct (silica, alumina, and diatomaceous earth) and reversed-phase (RP) (silica, alumina and diatomaceous earth impregnated with paraffin oil) TLC layers, and the plates were evaluated by a dual wavelength TLC scanner. The mean fraction was tentatively identified by on-line and off-line TLC-FTIR. The titration curve and strong binding of pigments to alumina indicated that each pigment fraction is of acidic character. Pigments showed anomalous retention behavior under RP-TLC conditions; retention decreased with increasing concentration of organic modifier in the mobile phase. The anomaly was tentatively explained by the suppression of dissociation of the highly polar groups of pigments, resulting in enhanced apparent lipophilicity. Multi-step gradient elution separated pigments on both silica and impregnated silica layers, the separation being better under RP conditions. Only the presence of a carbonyl group in the main fraction was verified by on-line FTIR, because the method requires a higher concentration of solutes than the TLC scanner did. Off-line FTIR spectra suggested that each pigment fraction contains -OH and -COO- groups, and that they are probably tannic acid like compounds.

Ion-pair formation of hydroquinine by chromatography

The study of hydroquinine, a Cinchona alkaloid, by analytical TLC (silica gel) in a mixture of dichloromethane and methanol (9/1, v/v) has shown that a new compound, with a higher R F value, is formed during the migration. Its structure has been elucidated and was shown to be the hydrochloride salt of the alkaloid, which behaves like a tight ion-pair. X-ray analysis showed the unit cell to contain two independent monoprotonated hydroquinine hydrochloride ion-pairs, as well as two independent benzene molecules from the crystallisation solvent. The chloride ion appeared to be trapped in a positive cavity between the protonated nitrogen of the quinuclidine ring and the methoxy group of the quinoline ring. The geometry of the salt may explain its apparent lipophilicity.

Modification of the apparent lipophilicity of steroidal drugs with gamma-cyclodextrin

The interaction between 17 steroidal drugs and gamma-cyclo-dextrin (gamma-CD) was determined by charge-transfer chromatography and the relative strength of interaction was calculated. The relationship between the strength of interaction and the physico-chemical parameters of steroidal drugs was elucidated with principal component analysis. Gamma-CD interacted with each steroidal drug decreasing the apparent hydrophobicity of the guest molecules. Calculations indicated that the interaction between the drugs and gamma-CD is of mixed character: steric, hydrophobic and electronic forces are involved in the complex formation. The marked influence of gamma-CD on the apparent hydrophobicity of drugs suggests that this interaction may modify the biological properties (absorption, uptake, half-life etc.) of drug-gamma-CD complexes resulting in modified efficacy.

Apparent thermodynamic parameters of ligand binding to the cloned rat μ-opioid receptor

The apparent thermodynamic parameters of binding of ten ligands to the cloned rat μ-opioid receptor stably expressed in Chinese hamster ovary (CHO) cells were investigated. For every ligand, the K d or K i values at 0°C, 12°C, 25°C and 37°C were determined, a van't Hoff plot was generated and Δ H°′, Δ S°′ and − TΔ S°′ and Δ G°′ were calculated. Changes in free energy (Δ G°′) ranged from −10.35 to −15.65 kcal/mol. The binding of sufentanil, ohmefentanyl, diprenorphine and d-Phe-Cys-Tyr- d-Trp-Arg-Thr-penicillamine-Thr-NH 2 (CTAP) was endothermic (Δ H°′>0) and driven by an increase in entropy (− TΔ S°′=−13.08 to −18.57 kcal/mol). The binding of naltrexone was exothermic (Δ H°′=−12.56 kcal/mol) and essentially enthalpy-driven. The binding of morphine, methadone, pentazocine, [ d-Ala 2, NMePhe 4, Gly-ol]enkephalin (DAMGO) and Tyr-Pro-NMePhe- d-Pro-NH 2 (PL017) was exothermic (Δ H°′=−3.53 to −9.95 kcal/mol) and occurred with an increase in entropy (− TΔ S°′=−2.48 to −7.92 kcal/mol). Plots of enthalpy versus entropy and enthalpy versus free energy were linear, although enthalpy–entropy compensation was not evident. The entropy changes were not correlated with apparent lipophilicity of the compounds. These results suggest that: (1) opioid ligands bind to the μ receptor by specific mechanisms, unrelated to lipid solubility; (2) the mechanism of binding is not universally different for peptide and non-peptide ligands; (3) the nature of binding does not a priori determine intrinsic activity. The results reveal a novel differentiation of opioid ligands into two groups (group 1: ohmefentanyl, sufentanil, diprenorphine, CTAP and PL017; group 2: naltrexone, morphine, methadone, DAMGO, pentazocine), based on two distinct relationships between enthalpy versus free energy of binding, the details of which are yet to be elucidated.

Effect of salts on the interaction of oxidized glutathione with dibasic amino acids.

The interaction of oxidized glutathione (GSSG) with dibasic amino acids was studied with charge-transfer chromatography carried out on unimpregnated cellulose layers in the absence and presence of LiCl, NaCl, KCl, MgCl2 and CaCl2. GSSG decreased in each case the apparent lipophilicity of dibasic amino acids, indicating some type of interaction. Calculations proved that the strength of GSSG - dibasic amino acid interaction decreases with increasing concentration of salts suggesting a hydrophilic character of interaction. It can be assumed that electrostatic forces between the carboxyl group of GSSG and the amino groups of amino acids are involved in the interaction. GSSG binds stronger to arginine than to lysine and ornithine suggesting that arginine is probably the primary binding site in proteins for GSSG.

( S)-4-amino-5-chloro-3-iodo-2-methoxy- N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide (TRIZAC), a high-affinity ligand for the 5-HT-3 receptor

TRIZAC is one of the most potent 5-HT-3 receptor antagonist reported to date, having 20-fold higher affinity than ( S)-5-todozacopride. This high affinity ( K 1 0.05 ± 0.01 nM) and a moderate apparent lipophilicity (log P app 2.12) makes TRIZAC a promising ligand for studying 5-HT-3 receptors.

Charge‐transfer chromatographic study of the interaction of commercial pesticides with hydroxypropyl‐β‐cyclodextrin

Abstract The interaction between 33 commercial pesticides with hydroxypropyI‐β‐cyclodextrin (HPBCD) was studied by charge‐transfer reversed‐phase thin‐layer chromatography using aqueous sodium chloride solutions as eluents. Each pesticide interacted with HPBCD, their lipophilicity linearly decreased with increasing HPBCD concentration, the pesticide ‐ HPBCD complex (probably inclusion complex) always being more hydrophilic than the uncomplexed pesticide. In many cases the retention of pesticide increased with increasing concentration of salt in the eluent. This effect can be tentatively explained by the suppression of the dissociation of the polar groups in the solute molecules resulting in increased apparent lipophilicity. No significant correlation was found between lipophilicity and complex stability or between salting‐out effect and lipophilicity, that is other than hydrophobic forces are involved in the pesticide ‐ HPBCD interaction.

Fluorinated benzamide neuroleptics—III. Development of ( S)- N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[ 18F]fluoropropyl)-2,3-dimethoxybenzamide as an improved dopamine D-2 receptor tracer

We have prepared five new analogs ( n-propyl, iso-propyl, allyl, n-butyl, and iso-butyl) of the dopamine D-2 receptor antagonist, FPMB which result from modifications of the ethyl group at the pyrrolidine nitrogen in FPMB. As expected, all new derivatives showed higher apparent lipophilicity (logK w), with iso-butyl being the most lipophilic (logK w = 2.52), followed by the allyl derivative (log K w = 2.43). The allyl group showed the largest increase in affinity (from 0.26 nM for the ethyl substituent to 0.03 nM for the allyl substituent, almost 10-fold), followed by the n-propyl substituent which showed approximately five-fold better affinity than did the ethyl substituent. Radiosynthesis of ( S)- N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-[ 18F]fluoropropyl)-2,3-dimethoxybenzamide ([ 18F]fallypride) was carried out by nucleophilic substitution reaction of ( S)- N-[(1-allyl-2-pyrrolidinyl)methyl]-5-(3-tosyloxypropyl)-2,3-dimethoxybenzamide with no carrier added 18F −. [ 18F]Fallypride was obtained in approximately 20–40% yields (EOS/EOB, decay corrected) in specific activities of 900–1700 Ci/mmol after reverse phase HPLC purification in 60 min from EOB. High striatal uptake (upto 2.5% injected dose/g) of [ 18F]fallypride in rats was observed with striatal/cerebellar ratios of 17, 42, 63 and 122 at 30, 60, 90 and 120 min post-injection, respectively. PET experiments with [ 18F]fallypride in a cebus monkey showed a brain uptake of 0.10% injected dose/cc. In rhesus monkeys [ 18F]fallypride showed rapid specific uptake in the striata (0.04-0.06% injected dose/cc) with striata/cerebellum ratios of approx. 3.0 at 14 min, 5.0 at 35 min and 8 at 70 min post-injection. Specifically bound [ 18F]fallypride was displaced with haloperidol (1 mg/kg) with a half-life of 18 min in the rhesus monkey.

Structure and interaction of inhibitors with the TEA/H+ exchanger of rabbit renal brush border membranes

The renal secretion of organic cations (OCs) involves a carrier-mediated exchange of OC for H+ in the luminal membrane of proximal cells. To assess the influence of chemical structure on the interaction of potential substrates with this process we examined the effect of a series of quaternary ammonium compounds on the transport of the OC tetraethylammonium (TEA) in a preparation of isolated renal brush-border membrane vesicles. Apparent inhibitory potency varied over a factor of 10(4), as expressed in inhibitor coefficients (KiTEA) whose approximate values ranged from 0.5 microM to 5 mM. The poorest inhibitors of TEA/H+ exchange were those molecules with carboxyl or hydroxyl residues, whereas the addition of methylene groups to a parent molecule tended to increase inhibitory potency. A plot of apparent KiTEA versus calculated octanol:water partition coefficient (expressed in terms of a relative lipophilicity factor) showed a clear correlation between these two parameters, although there was considerable variability between apparent lipophilicity and KiTEA for molecules with very different parent structures. For select groups of molecules with similar parent structures (e.g., the n-tetraalkylammoniums or the 4-phenylpyridinium, 3-phenylpyridinium, and quinolinium compounds) the correlation between calculated lipophilicity and apparent KiTEA was more marked. However, even within these groups of closely related parent structures, there appeared to be subtle, but systematic, variations in inhibitory potency that may have been related to the influence of steric factors on the binding of inhibitors to the TEA/H+ exchanger. We conclude that the lipophilic nature of a quaternary ammonium compound represents the predominant factor in the binding to and subsequent inhibition of, luminal TEA/H+ exchange. Specific steric factors may influence the binding of substrate to the exchanger, but play a secondary role in this interaction.

Reversed-phase thin-layer chromatography of various pesticides in the presence of water-soluble beta-cyclodextrin polymer

The modification of the hydrophobicity of 28 commercial pesticides with a water-soluble β-cyclodextrin polymer (SCDP) in the presence of aqueous NaCl has been studied by reversed-phase thin-layer chromatography. The pesticides formed inclusion complexes with SCDP and these complexes are less lipophilic than the parent pesticides. The sodium chloride exerted a typical saltingout effect, the retention of each pesticide increased with increasing concentration of the salt in the eluent. This effect can be tentatively explained by the suppression of the dissociation of the polar groups in the solute molecules resulting in increased apparent lipophilicity. The correlation between lipophilicity and salting-out effect was found to be significant, that is the salting-out effect increases with increasing polarity (lower lipophilicity) of the pesticides, whereas the lipophilicity has negligible influence on the inclusion-forming capacity of non-homologous series of pesticides.

Aromatic and Amine Substituent Effects on the Apparent Lipophiiicities of N-[(2-Pyrrolidinyl)methyl]-Substituted Benzamides

Lipophilic properties of 92 dopamine D-2 receptor antagonists belonging to the substituted benzamide class of compounds (orthopramides and methoxysalicylamides) were determined by oc- tadecylsilane reversed-phase HPLC. The apparent lipophilicity at pH 7.5 (log few) was obtained from the chromatographic capacity factors in 0.02M 3-(morpholino)propanesulfonic acid (MOPS) buffer at various concentrations of methanol. The experimental log Arw values were validated by comparison with the apparent octanol-water partitioning (log Papp) of 15 compounds of low to medium lipophilicity. The global lipophilicity of the neutral molecule (log few°) was obtained by correcting for ionization of the amine and the phenol, using known relationships for the effects on the pKa (where Ka is the dissociation constantS) of aromatic and aliphatic substituents. Multiple regression analysis showed that log few° can be expressed as the sum of π contributions and a cross correlation term (Σγσ) for interactions between the aromatic substituents. Comparison between the methoxysalicylamide (raclo- pride) series and the orthopramide (sulpiride) series demonstrated that an aromatic 6-hydroxy group increased log kw by 0.4 in the 5-halogen series and by 0.8 in the 5-alkyl series, and that a 6-methoxy group decreased log kw by 0.5. These paradoxical effects can be explained by the masking of the polarity of the amide caused by the 6-hydroxy group forming an intramolecular hydrogen bond with the amide carbonyl group. Introduction of an additional ortho-methoxy substituent had the opposite effect because the resulting steric hindrance prevents the amide moiety from adopting a coplanar conformation with the benzene ring. The presence of a substituent in the aromatic 3-position lowered log kw by 0.3 via a combination of steric and electronic influences on the adjacent 2-methoxy group, causing a weakening of the hydrogen bond between the amide and the oxygen atom of the 2- methoxy group. As a result, halogen and alkyl substituents in the 3- position increase the apparent lipophilicity only half that of similar substituents in the 5-position. Substitution with ω-fluoroalkoxyl groups in the aromatic 2- and 3-positions and with co-fluoroalkyl groups in the 5- position reduced lipophiiicities by 0.5 as compared with the corresponding desfluoro derivatives, thereby making them equivalent to an alkyl derivative with one less carbon atom in the chain. In contrast, substitution on the pyrrolidine nitrogen atom with a 2-fluoroethyl or a 3-fluoropropyl group produced compounds with apparent lipophiiicities ˜1.5 and ˜0.5 higher, respectively, than those of the corresponding W-ethyl derivatives. These effects result from a fluorine- induced decrease of the basicity of the amine. With these relationships, the apparent lipophiiicities at pH 7.4 were predicted for a series of recently developed benzamide radioligands to evaluate their utility as single photon emission computed topography and positron emission topography imaging agents of the dopamine D-2 receptor in the human brain.