Discovery of novel quaternary ammonium derivatives of (3R)-quinuclidinyl carbamates as potent and long acting muscarinic antagonists

Novel quaternary ammonium derivatives of N,N-disubstituted (3R)-quinuclidinyl carbamates have been identified as potent M₃ muscarinic antagonists with long duration of action in an in vivo model of bronchoconstriction. These compounds have also presented a high level of metabolic transformation (human liver microsomes). The synthesis, structure-activity relationships and biological evaluation of these compounds are reported.     

Tetrakis-azaaromatic quaternary ammonium salts: novel subtype-selective antagonists at neuronal nicotinic receptors that mediate nicotine-evoked dopamine release

A series of tetrakis-azaaromatic quaternary ammonium salts was synthesized to identify compounds with higher affinity and selectivity as antagonists at neuronal nicotinic receptor subtypes (nAChR) that mediate nicotine-evoked DA release. A high hit rate was achieved in identifying potent analogs that inhibit these nAChRs. Three tetrakis analogs, 11j, 11f, and 11g, were identified as potent (IC(50)=3, 28 and 56nM, respectively) antagonists at these receptors. These compounds represent a novel structural class of nicotinic receptor antagonists.     

Effect of a phenyl group in quaternary ammonium compounds on thiamine uptake in isolated rat hepatocytes

The inhibitory effect of a phenyl group in quaternary ammonium compounds on thiamine uptake in isolated rat hepatocytes was investigated. The phenyltrimethylammonium ion was a more potent inhibitor than the tetramethylammonium ion, while the dibenzyldimethylammonium ion was the most potent inhibitor of thiamine uptake among those compounds examined. A kinetic study showed that this compound was a competitive inhibitor. The cetyltrimethylammonium ion was a less effective inhibitor than the benzyltrimethylammonium ion, and the palmitoylcholine ion was a weak inhibitor. These results indicate that the lipophilicity of a quaternary ammonium compound is not always correlated with its affinity for thiamine-carrier binding, but the presence of a phenyl group plays a significant role in affinity. The inhibitory effect of the series of (CH₃)₃N⁺(CH₂)_nC₆H₅ (n = 0−6) compounds on thiamine uptake in isolated rat hepatocytes was studied. The maximal inhibitory activity occurred at n = 5. These results suggest that the phenyl group in a quaternary ammonium compound has a specific interaction with the thiamine-binding site in rat liver plasma membrane.     

Predictive screening model for potential vector-mediated transport of cationic substrates at the blood–brain barrier choline transporter

A set of semi-rigid cyclic and acyclic bis-quaternary ammonium analogs, which were part of a drug discovery program aimed at identifying antagonists at neuronal nicotinic acetylcholine receptors, were investigated to determine structural requirements for affinity at the blood–brain barrier choline transporter (BBB CHT). This transporter may have utility as a drug delivery vector for cationic molecules to access the central nervous system. In the current study, a virtual screening model was developed to aid in rational drug design/ADME of cationic nicotinic antagonists as BBB CHT ligands. Four 3D-QSAR comparative molecular field analysis (CoMFA) models were built which could predict the BBB CHT affinity for a test set with an r² <0.5 and cross-validated q² of 0.60, suggesting good predictive capability for these models. These models will allow the rapid in silico screening of binding affinity at the BBB CHT of both known nicotinic receptor antagonists and virtual compound libraries with the goal of informing the design of brain bioavailable quaternary ammonium analogs that are high affinity selective nicotinic receptor antagonists.     

Discovery of non-peptide, small molecule antagonists of α9α10 nicotinic acetylcholine receptors as novel analgesics for the treatment of neuropathic and tonic inflammatory pain

A series of azaaromatic quaternary ammonium analogs has been discovered as potent and selective α9α10 nicotinic acetylcholine receptor (nAChR) antagonists. The preliminary structure-activity relationships of these analogs suggest that increased rigidity in the linker units results in higher potency in inhibition of α9α10 nAChRs and greater selectivity over α7 nAChRs. These analogs represent a new class of analgesic for the treatment of neuropathic and tonic inflammatory pain.     

Quaternary ammonium substituted thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides: Potential membrane-impermeable inhibitors of carbonic anhydrase

Thieno[3,2-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides, which have a quaternary ammonium moiety incorporated into their structures, were synthesized. All of the quaternary ammonium salts prepared in the present study are potent inhibitors of both human carbonic anhydrase-II and recombinant human carbonic anhydrase-IV; they are significantly more potent as inhibitors of these carbonic anhydrase isozymes than the previously reported inhibitor quaternary ammonium homosulfanilamide. By virtue of the permanent cationic charge on these compounds they are anticipated to be membrane-impermeable inhibitors of carbonic anhydrase. Spiro quaternary ammonium compounds, such as 15 and 16, when formed by intracellular cyclization following transport of a suitable precursor molecule, such as 14, may be selective prolonged inhibitors of cytosolic carbonic anhydrase due to intracellular entrapment.     

Effects of atropine on the melanophores and light-reflecting chromatophores of some teleost fishes

1. The mechanism of the action of atropine, which is known to accelerate the dispersion response of fish melanophores, was examined by use of various receptor antagonists.2. The effects of atropine were found to be independent of adenosine receptors, beta-adrenoceptors and MSH receptors on the melanophore membrane.3. Analogs of atropine, such as scopolamine, also had a potent pigment-dispersing effect on melanophores, whereas the quaternary ammonium derivatives, which are positively charged molecules, had only a small effect.4. These results suggest that the possible site of atropine action is within the chromatophores themselves.5. In addition to the melanosome-dispersing effect, atropine caused a shift in the spectral peak of reflected light toward shorter wavelengths and the dispersion of leucosomes in the motile iridophores of the blue damselfish and in the leucophores of the medaka, respectively.     

Synthesis and analgesic activity of hydrochlorides and quaternary ammoniums of epibatidine incorporated with amino acid ester

Hydrochloride derivatives 5a–c and quaternary ammonium derivatives 6a–c of epibatidine incorporated with amino acid ester were synthesized and evaluated for their in vivo analgesic activity and toxicity. Among all tested compounds, compound 6c has the most potent analgesic activity. The quaternary ammonium salts 6a and 6c showed better analgesic activity than the corresponding hydrochlorides 5a and 5c. Both 5a–c and 6a–c showed significantly lower toxicity than epibatidine itself.     

Effet d'ammonium quaternaire halogène sur des cultures de cellules tumorales

This work reports the action of one halogenic quaternary ammonium compound on the in-vitro proliferation of different lines of human cancer cells. IC 50 inhibition growth was observed at a concentration of 2.10⁻⁶ mol and T1 growth at 3.10⁻⁶–5.10⁻⁵ mol. These results seem to indicate that halogenic quaternary ammoniums present a potent growth inhibitory activity on different cancer cells lines. The presence of a quaternary ammonium group, responsible for some alkylating effect, could explain such a result.     

Potent and selective CC-chemokine receptor-2 (CCR2) antagonists as a potential treatment for asthma

A number of compounds bearing a quaternary ammonium moiety were found to be antagonists with nanomolar binding affinity for the chemokine receptor-2. The structure-activity relationships in the series are described herein along with some detailed characterization of the interesting compounds.     

Diphenidol-related diamines as novel muscarinic M4 receptor antagonists

A series of hydrochloride derivatives 2a–9a and quaternary ammonium derivatives 3b–9b of diphenidol have been synthesized and characterized in receptor binding and cellular functional assays versus human muscarinic M₁–M₅ receptors expressed in CHO cells. Compound 8b, a methiodide derivative with a bipiperidinyl moiety and a second diphenidol framework, showed a potent and selective M₄ activity as competitive antagonist. Moreover 8b, acting as an allosteric modulator, was able to retard the dissociation rate of [³H]-N-methylscopolamine from CHO-M₄ cell membranes exposed to atropine. Taken together, these data suggest that 8b might open new avenues to the discovery of novel multivalent antagonists for the muscarinic receptors.     

Synthesis and structure–activity relationships of novel,substituted 5,6-dihydrodibenzo[a,g]quinolizinium P2X7 antagonists

Iminium quaternary protoberberine alkaloids (QPA) have been found to be novel P2X₇ antagonists. To assess their structure–activity relationships, these compounds were modified at their R¹ and R² groups and assayed for their ability to inhibit the 2′(3′)-O-(4-benzoylbenzoyl)-ATP (BzATP)-induced uptake of fluorescent ethidium by HEK-293 cells stably expressing the human P2X₇ receptor, and their ability to inhibit BzATP-induced IL-1β release by differentiated THP-1 cells. Compounds 15a and 15d, with alkyl groups at the R¹ position, and especially compound 19h, with the 2-NO₂-4,5-dimethoxy-benzyl group at the R² position, had potent inhibitory efficacy as P2X₇ antagonists.     

Nutritional constraints on displacement of Fusarium pseudograminearum from cereal straw by antagonists

Displacement of the fungus Fusarium pseudograminearum from stubble by antagonists is a potential means of biocontrol of crown rot in cereals. The role of carbon and nitrogen nutrition in interactions between the pathogen and the antagonists Fusarium equiseti, Fusarium nygamai, Trichoderma harzianum and the non-antagonistic straw fungus Alternaria infectoria was investigated. Sole carbon source utilization patterns on Biolog plates were similar among the three Fusarium species, suggesting a possible role for competition. However, carbon niche overlap was unlikely to be important in antagonism by T. harzianum. Straw medium supplemented with sugars generally reduced the inhibitory effect of antagonists on growth of F. pseudograminearum in dual culture, indicating that availability of simple carbon sources does not limit antagonism. Adding nitrogen as urea, nitrate or ammonium to straw medium had little effect on antagonism by F. equiseti and F. nygamai, but ammonium addition removed the inhibitory effect of T. harzianum on growth of F. pseudograminearum. Displacement of F. pseudograminearum from straw by all fungi in a Petri dish assay was greater when urea or nitrate was used as a nitrogen source than with ammonium. All forms of nitrogen significantly increased displacement of F. pseudograminearum from straw under simulated field conditions when straws were either inoculated with T. harzianum or exposed to resident soil microbes. However, in 2 out of 3 experiments urea and nitrate were more effective than ammonium. The results suggest that availability of nitrogen, but not carbon, is limiting the activities of antagonists of F. pseudograminearum in straw, and the way nitrogen is applied can influence the rate of displacement and mortality of the pathogen in host residues.     

Synthesis of quaternary ammonium salts of 16E-[4-(2-alkylaminoethoxy)-3-methoxybenzylidene]androstene derivatives as skeletal muscle relaxants

Synthesis of eighteen new quaternary ammonium salts of 16E-arylidene androstene derivatives as skeletal muscle relaxants is reported in the present study. The effects of possibly extended interonium distances on muscle relaxant activity are discussed. All the quaternary ammonium steroids produced reduction in the twitch responses, when screened for in vitro neuromuscular blocking activity using isolated chick biventer cervicis muscle preparation. However, the variable interonium distance, which is believed to range from 11 to 17 Å in these quaternary compounds and is associated with the built in flexibility of these structures about the single bonds on the moieties linked to ring D of the steroid skeleton, resulted in varied degrees of muscle relaxant activity. Some of the compounds also inhibited acetylcholinesterase activity in low concentrations so that they would not be directly suitable for use as muscle relaxants.     

Use of positively charged,leaving groups in the synthesis of α-D-linked galactosides. Attempted synthesis of 3-O-α-(D-(galactopyranosyl)-D-galactose

Quaternary ammonium and phosphonium salts were readily obtained by treating 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide with tertiary amines and phosphines in various solvents under anhydrous conditions. Optical rotations and n.m.r. spectra of the hygroscopic syrups indicated that they exist mainly in the β-D configuration. Several dialkyl sulfides reacted very slowly with the galactosyl bromide and no conclusive evidence for sulfonium salt formation was obtained. 2,3,4,6-Tetra-O-benzyl-α-D-galactopyranosyl chloride failed to react with any of the nucleophiles.Methanolysis reactions of the phosphonium salts were too slow to be practical and were not studied extensively. Methanolyses of several quaternary ammonium salts in various solvents were not completely stereospecific, but gave good yields of methyl 2,3,4,6-tetra-O-benzyl-α-D-galactopyranoside. Attempted reactions of benzyl 2-O-benzoyl-4,6-O-benzylidene-β-D-galactopyranoside with quaternary ammonium salts derived from 2,3,4,6-tetra-O-benzyl-α-D-galactopyranosyl bromide failed to produce the corresponding derivative of 3-O-(α-D-galactopyranosyl)-D-galactose.     

Sesquiterpene-α-amino acid quaternary ammonium hybrids from Stereum complicatum (Steraceae)

Five sesquiterpene-α-amino acid quaternary ammonium hybrids and the sesquiterpene core with no amino acid moiety linked were isolated from the n-butanol partition of the Stereum complicatum fungal culture grown on potato dextrose broth. Chemical structures were unambiguously elucidated by high resolution electrospray ionization mass spectrometry (HR-ESI-MS) in positive ion mode and NMR experiments and were identified as sterostrein Q and stereumamides A - E. The isolation and structure elucidation of these hybrid compounds is reported herein for the first time from S. complicatum. The phytotoxic, antifungal and antibacterial activities of these compounds were evaluated, but no significant activity was found. The HR-ESI-MS fragmentation pattern of the sesquiterpene-α-amino acid quaternary ammonium hybrid metabolites and its chemotaxonomic implication are discussed.     

Reactive extraction and reextraction of penicillin with different carriers

The extraction and reextraction of Penicillin G was investigated with different reactive components. The degrees E_R of reextraction and E_G extraction + reextraction were evaluated as a function of the pH value, carrier and penicillin concentrations. Besides Amberlite LA-2, nine different reactive components were tested and diisotridecylamine was found to be the most suitable one. The quaternary ammonium salt Adogen 464 is suitable also for the extraction of penicillin. However, the reextraction is incomplete. Therefore, sodium salt of p-toluene sulfonic acid was used as counter-ion, and it was regenerated by NaOH or Cl⁻ anion. The advantages of the use of quaternary ammonium salts are discussed.     

Resistance of Pseudomonas aeruginosa to amphoteric and quaternary ammonium biocides

Pseudomonas aeruginosa was able to grow in high levels of an amphoteric and a quaternary ammonium compound following repeated subculturing in increasing concentrations of the biocides. Resistance was acquired and lost gradually. Adaptation to both biocides resulted in cross resistance to biguanides but whereas quaternary adapted cells were resistant to a range of quaternary ammonium compounds, the amphoteric adapted organisms were not. Amphoteric adapted cells had increased hydrophobicity and exhibited ultrastructural modifications which suggested that the outer membrane might be involved in resistance. Both amphoteric and quaternary ammonium adapted organisms showed changes in their fatty acid profiles consistent with outer membrane modification but the changes were different in each case. The mechanisms involved in biocide resistance are discussed.     

The use of positively charged leaving-groups in the synthesis of α-D-linked glucosides. Synthesis of methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)-α-D-glucopyranoside

Quaternary ammonium and triphenylphosphonium salts of 2,3,4-tri-O-benzyl-6-O-(N-phenylcarbamoyl)-D-glucopyranosyl bromide were readily prepared by reaction with tertiary amines and triphenylphosphine under anhydrous conditions. Methanolysis of these salts was studied to determine the conditions of solvent and temperature that would produce the highest yields of α-D-glucosides. The quaternary ammonium salts gave the highest yields with solvents of low dielectric constant and room temperature. The phosphonium salts gave moderate yields with diethyl ether at 50°. The synthesis of methyl 2,3,4-tri-O-benzyl-6-O-(2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl)-α-D-glucopyranoside by treatment of the quaternary ammonium salt of 2,3,4,6-tetra-O-benzyl-α-D-glucopyranosyl bromide with methyl 2,3,4-tri-O-benzyl-α-D-glucopyranoside was studied as a model for the synthesis of oligosaccharides. The anomeric composition of the disaccharide product could be easily determined from the optical rotation since the specific rotations of both the final product and of the gentiobioside analog are known. Under the best conditions, the yield of disaccharide was low (50%) and the reactions were not completely stereoselective.