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PubMed2004

New FadB homologous enzymes and their use in enhanced biosynthesis of medium-chain-length polyhydroxyalkanoates in FadB mutant Escherichia coli.

Recombinant Escherichia coli harboring the medium-chain-length (MCL) polyhydroxyalkanoate (PHA) synthase gene has been shown to accumulate MCL-PHAs from fatty acids when FadB is inactive. However, the enzymes in fadB mutant E. coli responsible for channeling the beta-oxidation intermediates to PHA biosynthesis have not been fully elucidated. Only recently, two enzymes encoded by yfcX and maoC have been found to be partially responsible for this. In this study, we identified five new FadB homologous enzymes in E. coli: PaaG, PaaF, BhbD, SceH, and YdbU, by protein database search, and examined their roles in the biosynthesis of MCL-PHAs in an fadB mutant E. coli strain. Coexpression of each of these genes along with the Pseudomonas sp. 61-3 phaC2 gene did not allow synthesis of MCL-PHA from fatty acid in recombinant E. coli W3110, which has a fully functional beta-oxidation pathway, but allowed MCL-PHA accumulation in an fadB mutant E. coli WB101. In particular, coexpression of the paaG, paaF, and ydbU genes resulted in a MCL-PHA production up to 0.37, 0.25, and 0.33 g/L, respectively, from 2 g/L of sodium decanoate, which is more than twice higher than that obtained with E. coli WB101 expressing only the phaC2 gene (0.16 g/L). These results suggest that the newly found FadB homologous enzymes, or at least the paaG, paaF, and ydbU genes, are involved in MCL-PHA biosynthesis in an fadB mutant E. coli strain and can be employed for the enhanced production of MCL-PHA.

Amino Acid Sequence↗

PubMed2004

From the linden flower to linden honey--volatile constituents of linden nectar, the extract of bee-stomach and ripe honey.

Honey is produced by honeybees (Apis mellifera), which collect nectar from flowers, digest it in their bodies, and deposit it in honeycombs, where it develops into ripe honey. We studied the evolution of the volatile constituents from the nectar of linden blossoms (Tilia cordata) to honey via the 'intermediate' honeybee. The sampling of the contents of the honey stomach or honey sack of the bee is unique. Extracts were prepared from nectar, from the liquid of the honey stomach, and from ripe honey. The chemistry is extremely complex, and compounds spanning from monoterpenes (hydrocarbons, ethers, aldehydes, acids, and bifunctional derivatives), isoprenoids, aromatic compounds (phenylpropanoids, phenols), and products degraded from fatty acids to alkaloids, were identified. Some compounds definitely stem from the plants, whereas other interesting constituents can be attributed to animal origin. Two derivatives of decanoic acid, 9-oxodec-2-enoic acid (12) and 9-hydroxydec-2-enoic acid, identified in the honey are known to be constituents of the so-called 'Queen's pheromone'. Two metabolites of these acids were identified in the extract of the honey stomach: 8-oxononanal (10), a new natural product, and 8-oxononanol (11). There structures were confirmed by synthesis. Nectar and honey stomach contain many aldehydes, which, due to the highly oxidative atmosphere in the honeycomb, are found as corresponding acids in the honey. Two acids were newly identified as 4-isopropenylcyclohexa-1,3-diene-1-carboxylic acid (14) and 4-(1-hydroxy-1-methylethyl)-cyclohexa-1,3-diene-1-carboxylic acid (15).

Animals↗

PubMed2006

The venomous secrets of the web droplets from the viscid spiral of the orb-weaver spider Nephila clavipes (Araneae, Tetragnatidae).

The capture web of N. clavipes presents viscous droplets, which play important roles in web mechanics and prey capture. By using scanning and transmission electron microscopy, it was demonstrated that the web droplets are constituted of different chemical environments, provided by the existence both of an aqueous and a lipid layer, which, in turn, present a suspension of tenths of vesicles containing polypeptides and/or lipids. GC/EI-MS Analysis of the contents of these vesicles led to the identification of some saturated fatty acids, such as decanoic acid, undecanoic acid, dodecanoic acid, tetradecanoic acid, octadecanoic acid, and icosanoic acid, while other components were unsaturated fatty acids, such as (Z)-tetradec-9-enoic acid, (Z)-octadec-9-enoic acid, and (Z)-icosa-11-enoic acid; and polyunsaturated fatty acids like (9Z,12Z)-octadeca-9,12-dienoic acid, (9Z,12Z,15Z)-octadeca-9,12,15-trienoic acid, and (11Z,14Z)-icosa-11,14-dienoic acid. Toxic proteins such as calcium-activated proteinase and metalloproteinase jararhagin-like precursor were also identified by using a proteomic approach, indicating the possible involvement of these enzymes in the pre-digestion of spiders' preys web-captured. Apparently, the mixture of fatty acids are relatively toxic to insects by topical application (LD50 64.3+/-7.6 ng mg(-1) honeybee), while the proteins alone present no topical effect; however, when injected into the prey-insects, these proteins presented a moderate toxicity (LD50 40.3+/-4.8 ng mg(-1) honeybee); the mixture of fatty acids and proteins is very toxic to the preys captured by the web droplets of the viscid spiral of Nephila clavipes when topically applied on them (LD50 14.3+/-1.8 ng mg(-1) honeybee).

Amino Acid Sequence↗

PubMed2003

Novel trifluoromethyl ketones as potent gastric lipase inhibitors.

Novel inhibitors of human digestive lipases, lipophilic trifluoromethyl ketones, were developed. These analogues of the natural triacylglycerol substrates of lipases were designed to contain the carbonyl group of the trifluoromethyl ketone functionality in place of the carbonyl group of the scissile ester bond at the sn-1 position. The ester bond at the sn-3 position was replaced by an ether bond, while the secondary hydroxy group was either esterified or etherified. The inhibitors were prepared starting from solketal. The inhibition of human pancreatic and gastric lipases by the trifluoromethyl ketones was studied by the monolayer technique. 5,5,5-Trifluoro-1-(dodecyloxymethyl)-4-oxopentyl decanoate is the best synthetic inhibitor of human gastric lipase ever reported (inhibition constant alpha(50)=0.003).

Enzyme Inhibitors↗

PubMed2007

Learning from directed evolution: Further lessons from theoretical investigations into cooperative mutations in lipase enantioselectivity.

An earlier experimental study, which involved the directed evolution of enantioselective lipase variants from Pseudomonas aeruginosa as catalysts in the hydrolytic kinetic resolution of 2-methyl-decanoic acid p-nitrophenyl ester, provided a mutant with six mutations. Consequently, the selectivity factor was found to increase from E = 1.1 for the wild-type to E = 51 for the best mutant. Only one of the amino acid exchanges in this mutant was found to occur next to the binding pocket, the other mutations being remote. Our previous theoretical analysis with molecular-dynamics simulations helped to unveil the source of enhanced enantioselectivity: a relay mechanism that involves two of the six mutations was shown to induce strong cooperativity. In this investigation, single, double, and triple mutants were constructed and tested as enantioselective catalysts. This study supports our original postulate regarding the relay mechanism, offers further mechanistic insight into the role of individual mutations, and provides mutants that display even higher enantioselectivity (E of up to 64).

Catalysis↗

PubMed1986

Effects on the behavior of infant common marmosets (Callithrix jacchus) of separation from caregivers and of drug-induced reduction in caregiver responsiveness.

The effects of separating 4-week-old twin marmosets for 8 days from their families are compared with the effects of leaving 4-week-old infants with their families, but reducing the responsiveness of their caregivers for 8 days by administration of the tranquilizer fluphenazine decanoate. Both treatments reduce infant mobility, abolish play, and increase the time that infants spend with each other. During the period after the termination of the treatment, both treatment groups continue to play and move less than controls, and try to climb onto the mothers more frequently. These results are consistent with the hypothesis that the principal factor precipitating disturbed behaviors in infant monkeys subjected to long-term separation is disruption of the infant-caregiver relationship rather than the separation itself. Some post-treatment differences occur between separated and tranquilized groups. Notably, reunion after separation appears to involve a marked readjustment of the behavior of all family members to the return of the infants, whereas withdrawal of the tranquilizer does not.

Animals↗

PubMed1990

Effect of exogenous fatty acids on lipid synthesis, marker-enzymes, and development of glial cells maintained in serum-free culture.

Glial cells were isolated from the cerebra of 7-day-old rats and maintained in culture in a chemically defined medium that favours the development of oligodendrocytes. Acetate, butyrate, or albumin-bound hexanoate, octanoate, decanoate, laurate, myristate, palmitate, oleate, linoleate, or arachidonate was added to the culture medium. The incorporation of [3H]acetate into fatty acids and cholesterol and [35S]sulphate into sulphatide, and the activities of the oligodendrocyte marker enzymes 2',3'-cyclic-nucleotide 3'-phosphodiesterase and glycerol 3-phosphate dehydrogenase were measured. The composition of the glial cell population (the number of astrocytes and oligodendrocytes) in these cultures was studied by immunocytochemistry. Results show that 1) long-chain fatty acids depress the synthesis of fatty acids, cholesterol, and sulphatide; and 2) the presence of long-chain, in contrast to short-chain, fatty acids in the culture medium lowers the activities of 2',3'-cyclic-nucleotide 3'-phosphodiesterase and glycerol 3-phosphate dehydrogenase and decreases the number of oligodendrocytes. Our results suggest that long-chain fatty acids exert a negative influence on the development of oligodendrocytes in the culture system used.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗

PubMed2003

Structure-activity relationship for chemical skin permeation enhancers: probing the chemical microenvironment of the site of action.

Studies were previously conducted in our laboratory on the influence of n-alkanols, 1-alkyl-2-pyrrolidones, N,N-dimethlyalkanamides, and 1,2-alkanediols as skin permeation enhancers on the transport of a model permeant, corticosterone (CS). The experiments were conducted with hairless mouse skin (HMS) in a side-by-side, two-chamber diffusion cell, with enhancer present in an aqueous buffer in both chambers. The purpose of the present study was to extend these studies and investigate in greater detail the hypothesis that a suitable semipolar organic phase may mimic the microenvironment of the site of enhancer action, and that the enhancer partitioning tendency into this organic phase may be used to predict the enhancer potency. CS flux enhancement along the lipoidal pathway of HMS stratum corneum was determined with the 1-alkyl-2-azacycloheptanones, 1-alkyl-2-piperidinones, 1,2-dihydroxypropyl decanoate, 1,2-dihydroxypropyl octanoate, n-alkyl-beta-D-glucopyranosides, 2-(1-alkyl)-2-methyl-1,3-dioxolanes, 1,2,3-nonanetriol, and trans-hydroxyproline-N-decanamide-C-ethylamide as enhancers. Enhancement factors (E values) were calculated from the permeability coefficient and solubility data over a range of E values. Comparisons of the enhancer potencies for all studied homologous series and the carbon number of the n-alkyl group revealed a nearly semilogarithmic linear relationship with a slope of approximately 0.55, which is consistent with the hydrophobic effect. Moreover, comparisons of the enhancer potencies of all the enhancers with the n-hexanol-phosphate buffered saline (PBS), n-octanol-PBS, n-decanol-PBS, and n-hexane-PBS partition coefficients showed very good correlations for the n-alkanol solvents but not for n-hexane. This result supports the interpretation that the enhancer potency is directly related to the ability of the enhancer molecule to translocate to a site of action via its free energy of transfer from the bulk aqueous phase to a semipolar microenvironment in the stratum corneum lipid lamella that is well mimicked by water-saturated n-alkanols.

Adjuvants, Pharmaceutic↗

PubMed1975

Hydrolysis of fatty acid esters of acetaminophen in buffered pancreatic lipase systmes I.

A series of fatty acid esters of acetaminophen were prepared beginning with acetate, the propionate, and all even-numbered fatty acids and going through the octadecanoate. The enzymatic hydrolysis of all derivatives was studied in vitro with varying amounts of lipase assed to the hydrolysis mixtures. Under the conditions of the in vitro hydrolysis, it was observed that all derivatives were hydrolyzed more readily in an aqueous medium at pH 7.8. A positive relationship was seen between the hydrolysis rates and the concentration of lipase at this pH. There was a negative relationship between the chain length of the acyl moiety and the corresponding hydrolysis rates. The short chain esters were hydrolyzed at rates many times more rapid than the long chain esters. The intermediate chain-lenght ester, p-acetamidophenyl decanoate, p-acetamidophenyl laurate, and p-acetamidophenyl myristate, were hydrolyzed at intermedediate time periods extending over 12 hr, approaching completion at 97.5, 87.5, and 80.5%, respectively, when 18 Wilson units of lipase was used in each milliliter of hydrolysis mixture. The longer chain esters, p-acetamidophenyl palmitate and p-acetamidophenyl stearate, were hydrolyzed to the extent of 16 and 8%, respectively, over 12 hr under the same in vitro conditions.

Acetaminophen↗

PubMed1977

Prostaglandin monolayers II: monomolecular film behavior of dinoprost C-15 alkyl esters.

Monomolecular film compression-relaxation behavior was examined for select dinoprost C-15 alkyl esters. Higher homologs of the series such as palmitate and decanoate esters yielded stable expanded monolayers that exhibited minimal relaxation of surface pressure during noncompression. Their limiting molecular areas were consistent with a Hirschfelder model projection in which the prostaglandin moiety assumes a horizontal orientation at the interface with its alkyl ester chain oriented vertical to the surface plane. Shorter chain homologs such as hexanoate, valerate, butyrate, propionate, and acetate also formed expanded monolayers but exhibited increased instability with decreased alkyl chain length, as reflected in their lower surface pressure development during compression and significant relaxation of pressure during noncompression. Such instability can be tied to their increased solubility in the subphase solution and higher desorption rate from the interface.

Chemical Phenomena↗

PubMed1988

A highly sensitive and specific radioimmunoassay for quantitation of plasma fluphenazine.

Antisera of high sensitivity and selectivity were obtained from rabbits immunized with conjugates of hemisuccinylated fluphenazine and porcine thyroglobulin. The antiserum selected (titer 1:6000) for the development of the RIA was obtained after a priming dose and a single iv booster injection three months later. This antiserum had negligible crossreactivity with known available metabolites of fluphenazine (FPZ) and an affinity constant of 2 X 10(10) L/mol. Tritiated FPZ was further purified by HPLC and used as a ligand. The method detects as little as 20 pg/mL of plasma (4 pg/RIA tube) after 1 mL of plasma is extracted. The extraction was performed at a basic pH with heptane: isoamyl alcohol (99:1); the solvent was then back extracted using an acetic phosphate buffer. Recoveries were uniformly high (88.6 +/- 2.1%), and this aqueous buffer extract was used directly in the RIA procedure. The assay has intra- and interassay coefficients of variation of 5.8 and 8.2%, respectively, in a plasma concentration of 95 pg/mL. Results using this procedure have been cross validated against an HPLC procedure (r = 0.952, slope = 1.032, intercept = 0.009, n = 18). In a single-dose FPZ study (10 mg, po), plasma FPZ levels in 25 normal volunteers could be monitored greater than 48 h post dose. Single plasma level profiles, after an initial injection of 12.5 mg of FPZ decanoate, could be measured greater than 36 d, and, in some cases, up to 100 d post dose.

Administration, Oral↗

PubMed1992

Lipidic peptides. V: Penicillin and cephalosporin acid conjugates with increased lipophilic character.

Lipophilic, double-ester derivatives of beta-lactam antibiotics with methylene, ethylene, and propylene spacers were prepared by crown-ether-assisted coupling of halogenoalkyl esters of 2-(tert-butoxycarbonylamino)decanoic acid to either penicillin G or cefuroxime. The hydroxyethyl ester of penicillin G and the tert-butoxypropyl ester of cefuroxime were also prepared. The lipophilic, double-ester conjugates, the hydroxyethyl ester of penicillin G, and the tert-butoxypropyl ester of cefuroxime showed weak or no antibiotic activity in vitro, as expected. The lipophilic penicillin G conjugates and the tert-butoxypropyl ester of cefuroxime were active in vivo against a nonpenicillinase-producing strain of Staphylococcus aureus after subcutaneous administration. The penicillin G double ester with propylene spacer and the tert-butoxypropyl ester of cefuroxime were inactive in vitro, a fact indicating that both compounds were hydrolyzed in vivo, as desired. After oral administration, the lipophilic, double-ester conjugate of penicillin G with methylene spacer and the tert-butoxypropyl ester of cefuroxime were active.

Administration, Oral↗

PubMed2002

Tardive dyskinesia model in the common marmoset.

Thirteen adult common marmosets (Callithrix jacchus) were given once-monthly injections of haloperidol decanoate (5-15 mg/kg i.m.) for one year. Thereafter, drug-free and treatment periods alternated at 3-month intervals. After 2.5 to 14 months, 12 monkeys showed symptoms of tardive dyskinesia (TD), such as periocular and perioral twitchings, tongue protrusions, masticatory movements, and choreic movements in arms and legs. When TD symptoms were evident, the periodic treatment was interrupted and symptoms persisted for at least 5 months after the last haloperidol dose, worsened by injection of the anticholinergic drug biperiden. An injection of nondepot haloperidol (0.12 or 0.25 mg/kg) produced a reduction of TD symptoms. At the end of the study, nondepot haloperidol was injected once a week at two doses (0.12 and 0.25 mg/kg i.m.). A syndrome of excitation with peculiar behavior, interpreted as acute dystonia, was precipitated in all animals. The animals showed sustained retrocollis, climbing upside down, biting the perch, repetitive turnings, and frequent backward movements. The dystonic movements lasted approximately 6 hours and were reduced but not completely extinguished by biperiden (0.1 mg/kg). The TD syndrome registered in marmosets may provide a useful model for screening new antipsychotics for their propensity to induce TD.

Animals↗

PubMed1995

Crystallization and preliminary diffraction studies of thioesterase II from rat mammary gland.

Thioesterase II from rat mammary gland has been crystallized in the presence of decanoic acid by the vapor diffusion method. The crystals belong to the orthorhombic space group P2(1)2(1)2(1), and have cell dimensions, a = 52.7 A, b = 78.0 A, and c = 133.6 A. The asymmetric unit likely consists of two protein monomers based on predictions from its calculated Matthews coefficient. Crystals typically diffract to at least 2.5 A resolution and are suitable for X-ray crystallographic analysis.

Animals↗

PubMed2001

D2 but not D3 receptors are elevated after 9 or 11 months chronic haloperidol treatment: influence of withdrawal period.

Previous postmortem studies have identified divergent alterations in D2 and D3 receptors in schizophrenia but those results cannot be interpreted without further understanding of whether antipsychotic regulation of the D3 receptor is different from that of the D2 receptor. Depot parenteral administration of haloperidol decanoate was utilized to achieve consistent high levels in rat brain for 9 months with 2-month withdrawal or 11 months with 48-h withdrawal and compared to vehicle control and acute haloperidol (48-h) treatment groups. Autoradiographic means for measuring levels of D2 ([(3)H]-spiperone) and D3 receptors ([(125)I]trans 7-OH-PIPAT) and of D3 mRNA by in situ hybridization histochemistry in rat caudate-putamen, nucleus accumbens, islands of Calleja, and olfactory tubercle determined that there were significant group differences for regulation of D2 receptor. Chronic haloperidol for 9 or 11 months elevated D2 but not D3 receptors or D3 mRNA in all regions measured. Acute haloperidol treatment had no significant effects for any measure. Treatment for 9 months with a 2-month withdrawal resulted in a persistent increase in D2 receptors that was greater than that observed in the 11 months with 48-h withdrawal. This effect was most noticeable in the olfactory tubercle. These data confirm previous findings that short- or long-term haloperidol treatment leads to elevations in D2 but not D3 receptors or D3 mRNA, and long-term withdrawal from chronic haloperidol does not lead to elevations in D3 receptors or D3 mRNA. This suggests that an elevation in D3 receptors identified at postmortem in schizophrenics withdrawn from antipsychotics is not the result of the previous drug history [Gurevich et al. (1997) Arch Gen Psychiatry 54:225-232].

Animals↗

PubMed1994

The effects of chronic haloperidol administration on GABA-immunoreactive axon terminals in rat medial prefrontal cortex.

Several reports have suggested that chronic haloperidol (HAL) treatment induces ultrastructural changes in synapses of substantia nigra, corpus striatum, and medial prefrontal cortex (mPFC) of rat brain. The effects of HAL on specific cortical transmitter systems, however, are not well characterized. Recent studies have indicated that there may be a loss of gamma-aminobutyric acid (GABA)ergic cells in anterior cingulate cortex of schizophrenic subjects and this hypothesis has prompted interest in the question of whether dopamine receptor antagonists, such as HAL, may influence the activity of this transmitter system. This current report describes a quantitative light microscopic analysis of GABA-immunolabeled axosomatic terminals in mPFC of rats treated with HAL decanoate (0.5 mg/kg/day, i.m.) for a period of 4 months. GABA-containing terminals were visualized with an avidin-biotin immunoperoxidase method for localizing anti-GABA antibodies. Computer-assisted image processing was employed to determine the total number of pixels representing GABA-immunoreaction product in axon terminals that were in direct apposition to pyramidal cell bodies. Drug-treated animals showed a significant increase in the number of pixels representing GABA-immunoreaction product in axosomatic terminals of layers II, III, VI, and VI (93%, 63%, 31%, and 43%, respectively). These data are consistent with the idea that chronic HAL administration may be associated with a significant increase in the amount of GABA present in terminals surrounding pyramidal neurons of rat mPFC. The fact that GABA-containing terminals showed the greatest increase in layer II is not consistent with the known distribution of dopamine afferents to this region which is lowest in superficial laminae. Based on the laminar distribution of non-dopaminergic receptor types that have a high affinity for HAL, the effect of this drug on GABAergic transmission could potentially involve changes that are mediated through mechanisms in which 5-HT2 or sigma opiate receptors play a role.

Animals↗

PubMed1994

Alterations in mRNA levels of D2 receptors and neuropeptides in striatonigral and striatopallidal neurons of rats with neuroleptic-induced dyskinesias.

Chronic neuroleptic treatment in rat produces vacuous chewing movements (VCMs), analogous to TD in humans. We hypothesized that these hyperkinetic movements were due to alterations in striatonigral and striatopallidal GABAergic spiny II neurons. Rats were treated for 36 weeks with haloperidol decanoate and withdrawn for 28 weeks. Striatonigral and striatopallidal neurons were assessed using in situ hybridization histochemistry for mRNA levels of D1 and D2 dopamine receptors, preproenkephalin (ENK), prodynorphin (DYN), protachykinin (substance P), and glutamate decarboxylase (GAD67) in the dorsolateral and ventromedial striatum as well as the nucleus accumbens. Rats that did not develop VCMs (-VCM) had increased D2 receptor and DYN mRNA, and reduced substance P mRNA in the dorsolateral striatum. Rats with persistent VCMs (+VCM) had increased D2 receptor, ENK, and DYN mRNA in both striatal regions, and increased ENK and DYN mRNA in the nucleus accumbens, compared with controls. Relative to -VCM rats, however, +VCM rats only had increased ENK mRNA in the nucleus accumbens. Considering the overall pattern of mRNA changes, the data suggest that alterations in both the D1-mediated striatonigral and the D2-mediated striatopallidal pathways play a role in the expression of the VCM syndrome. To the extent that gene expression parallels changes in neuronal activity, this implies that the VCM syndrome is associated with increased activity in both pathways.

Animals↗

PubMed1997

Heme-coordinating analogs of lauric acid as inhibitors of fatty acid omega-hydroxylation.

A series of omega-substituted fatty acids with potential heme-coordinating groups was synthesized as inhibitors of lauric acid omega-hydroxylation. The compounds were evaluated using liver microsomes from clofibrate (CF)-induced rats and an engineered expressed CYP4A1-derived fusion protein called f4A1. omega-Imidazolyl-decanoic acid (compound 11) and omega-aminolauric acid (compound 7) were potent Type II ligands and potent inhibitors of lauric acid omega-hydroxylation in both CF-microsomes and f4A1. Replacing their terminal amino or imidazolyl groups with other potential iron-binding groups such as omega-methylsulfinyl-, omega-cyano-, omega-azido-, or omega-formamido all greatly reduced their potency as inhibitors of omega-hydroxylation and their affinity for cytochrome P450 as measured by Ks values. In CF-microsomes, inhibition of (omega-1)-hydroxylation of lauric acid by a homologous series of omega-imidazolyl-alkanoic acids varied only 2-fold but in the same incubations inhibition of omega-hydroxylation increased 22-fold upon going from C-8 to C-12. A similar dependence of binding affinity and inhibitory potency on chain length was also seen in the f4A1 system. In contrast, chain length had little effect on activity among n-alkylamines or N-alkylimidazoles lacking a carboxyl or other polar functional group, suggesting that 7, 11, and related bifunctional compounds interact with CYP4A1 in CF-microsomes and with f4A1 in a specific bidentate fashion. Imidazoles containing phenyl, benzyl, or phenylethyl substituents at N-1 interact less strongly than related N-alkyl-imidazoles of similar carbon number and hydrophobicity, suggesting that the steric bulk and/or rigidity of the phenyl ring is not well accommodated in the active site.

Animals↗