Metal-Organic Framework with Dual Active Sites in Engineered Mesopores for Bioinspired Synergistic Catalysis.

Here we report the design of an enzyme-inspired metal-organic framework (MOF), 1-OTf-Ir, by installing strong Lewis acid and photoredox sites in engineered mesopores. Al-MOF (1), with mixed 2,2'-bipyridyl-5,5-dicarboxylate (dcbpy) and 1,4-benzenediacrylate (pdac) ligands, was oxidized with ozone and then triflated to generate strongly Lewis acidic Al-OTf sites in the mesopores, followed by the installation of [Ir(ppy)2(dcbpy)]+ (ppy = 2-phenylpyridine) sites to afford 1-OTf-Ir with both Lewis acid and photoredox sites. 1-OTf-Ir effectively catalyzed reductive cross-coupling of N-hydroxyphthalimide esters or aryl bromomethyl ketones with vinyl- or alkynyl-azaarenes to afford new azaarene derivatives. 1-OTf-Ir enabled catalytic synthesis of anticholinergic drugs Pheniramine and Chlorpheniramine.

Pyrazole[3,4-d]pyridazine derivatives: Molecular docking and explore of acetylcholinesterase and carbonic anhydrase enzymes inhibitors as anticholinergics potentials.

Recently, the pyridazine nucleus has been widely studied in the field of particular and new medicinal factors as drugs acting on the cardiovascular system. Additionally, a number of thienopyridazines have been claimed to possess interacting biological macromolecules and pharmacological activities such as NAD(P)H oxidase inhibitor, anticancer, and identified as a novel allosteric modulator of the adenosine A1 receptor. The literature survey demonstrates that coumarin, 1,2-pyrazole benzothiazole, and 1,3- thiazole scaffolds are the most versatile class of molecules. In this study, a series of substituted pyrazole[3,4-d]pyridazine derivatives (2a-n) were prepared, and their structures were characterized by Mass analysis, NMR, and FT-IR. These obtained pyrazole[3,4-d]pyridazine compounds were very good inhibitors of the carbonic anhydrase (hCA I and II) isoenzymes and acetylcholinesterase (AChE) with Ki values in the range of 9.03 ±â€¯3.81-55.42 ±â€¯14.77 nM for hCA I, 18.04 ±â€¯4.55-66.24 ±â€¯19.21 nM for hCA II, and 394.77 ±â€¯68.13-952.93 ±â€¯182.72 nM for AChE, respectively. The possible inhibition mechanism of the best-posed pyrazole[3,4-d]pyridazine and pyrazole-3-carboxylic acid derivatives and their interaction with catalytic active pocket residues were determined based on the calculations.

Synthesis and characterization of novel bromophenols: Determination of their anticholinergic, antidiabetic and antioxidant activities.

In this paper, a series of novel bromophenol derivatives were synthesized and evaluated for their acetylcholinesterase and α-glycosidase enzymes inhibition properties and antioxidant activity. Diarylmethanones were synthesized and their bromination was carried out. During bromination, some compounds gave new bromophenols via regioselective O-demethylation. Demethylation of brominated diarylmethanones was also performed with BBr3 to give novel bromophenols. In addition, we examines the antioxidant capacity of novel bromophenol derivatives using several in vitro bioanalytical methodologies such as 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS⋅+) and 1,1-diphenyl-2-picryl-hydrazyl free radical (DPPH) radical scavenging activity, Fe3+ and Cu2+ reducing activities and ferrous (Fe2+) ions chelating activities. Also, novel bromophenols and methoxylated bromophenols derivatives were tested against acetylcholinesterase and α-glycosidase, which associated with some metabolic diseases. The novel bromophenols showed Ki values in range of 8.94 ±â€¯0.73-59.45 ±â€¯14.97 nM against AChE and 4.31 ±â€¯1.93-44.14 ±â€¯2.19 nM against α-glycosidase.

The first synthesis, carbonic anhydrase inhibition and anticholinergic activities of some bromophenol derivatives with S including natural products.

Starting from vanillin, known four benzyl bromides with Br were synthesized. The first synthesis of natural product 3,4-dibromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (2) and 3,4,6-tribromo-5-((methylsulfonyl)methyl)benzene-1,2-diol (3) and derivatives were carried out by demethylation, acetylatilation, oxidation and hydrolysis reactions of the benzyl bromides. Also, these compounds were tested against some important enzymes like acetylcholinesterase and butyrylcholinesterase enzymes, carbonic anhydrase I, and II isoenzymes. The novel bromophenols showed Ki values of in range of 53.75 ±â€¯12.54-234.68 ±â€¯46.76 nM against hCA I, 42.84 ±â€¯9.36 and 200.54 ±â€¯57.25 nM against hCA II, 0.84 ±â€¯0.12-14.63 ±â€¯3.06 nM against AChE and 0.93 ±â€¯0.20-18.53 ±â€¯5.06 nM against BChE. Induced fit docking process performed on the compounds inhibiting hCA I, hCA II, AChE, and BChE receptors. Hydroxyl group should exist at the aromatic ring of the compounds for inhibition of the enzymes. The moieties reported in this study will be useful for design of more potent and selective inhibitors against the enzymes.

Novel tribenzylaminobenzolsulphonylimine based on their pyrazine and pyridazines: Synthesis, characterization, antidiabetic, anticancer, anticholinergic, and molecular docking studies.

A new method of obtaining multifunctional pyrazoles by the reaction of 1,3-dipolar addition of tribenzylsulfonyliminochloride to polarophiles has been developed. This imine is obtained by reacting tribenzylamine with N-chlorobenzene sulfamide (chloramine-B). Regardless of the structure and composition of polarophiles, the cyclization reaction takes place in the presence of alkali in 6-8 h of boiling, which proves the activation of the methylene groups of tribenzylamine using the electron-withdrawing sulfonamide group. These novel derivatives were effective inhibitors of the α-glycosidase, butyrylcholinesterase (BChE), and acetylcholinesterase enzymes (AChE) with Ki values in the range of 0.45 ±â€¯0.08-1.24 ±â€¯0.27 µM for α-glycosidase, 6.04 ±â€¯0.95-11.61 ±â€¯2.84 µM for BChE, and 2.04 ±â€¯0.24-4.23 ±â€¯1.02 µM for AChE, respectively. The biological activities of the studied molecules against enzyme molecules were investigated by molecular docking calculations. The enzymes studied were AChE for ID 4M0E, BChE for ID 5NN0 BChE, and α-Glycosidase for ID 1XSI (α-Gly) respectively.

Novel eugenol bearing oxypropanolamines: Synthesis, characterization, antibacterial, antidiabetic, and anticholinergic potentials.

Five oxypropanol amine derivatives that four of them are novel have been synthesized with high yields and practical methods. in vitro antibacterial susceptibility of Acinetobacter baumannii, Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus strains to synthesized substances were evaluated with agar well-diffusion method by comparison with commercially available drugs. Most of the bacteria were multidrug resistant. It was concluded that these compounds are much more effective than reference drugs. These eugenol bearing oxypropanolamine derivatives were also effective inhibitors against α-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with Ki values in the range of 0.80 ±â€¯0.24-3.52 ±â€¯1.01 µM for hCA I, 1.08 ±â€¯0.15-3.64 ±â€¯0.92 µM for hCA II, 5.18 ±â€¯0.84-12.46 ±â€¯2.08 µM for α-glycosidase, and 11.33 ±â€¯2.83-32.81 ±â€¯9.73 µM for AChE, respectively.

Synthesis, crystal structure, and biological evaluation of optically active 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-3-carbonitriles: Antiepileptic, antidiabetic, and anticholinergics potentials.

In the presence of chiral organic catalysts, the optically active 4H-chromine was synthesized from the multicomponent condensation of 5,5-dimethylcyclohexane-1,3-dione with malononitrile and methylene-active compound, and the specific angle of rotation of the compounds was determined in the AUTOPOL-III polarimeter and their structures were confirmed by the X-ray spectroscopic analysis method. These optically active 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromen-3-carbonitriles were effective inhibitors of α-glycosidase, the cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase (AChE) enzymes with Ki values in the range of 21.33 ± 1.11 to 40.24 ± 10.78 µM for hCA I, 28.91 ± 6.51 to 59.97 ± 15.62 µM for hCA II, 18.16 ± 3.18 to 66.57 ± 1.36 µM for α-glycosidase, and 8.68 ± 0.93 to 102.61 ± 24.96 µM for AChE.

Aminopyrazole-substituted metallophthalocyanines: Preparation, aggregation behavior, and investigation of metabolic enzymes inhibition properties.

The synthesis, characterization, aggregation behavior, theoretical studies, and investigation of antimicrobial, antidiabetic, and anticholinergic properties of 4-(2-(5-amino-4-(4-bromophenyl)-3-methyl-1H-pyrazol-1-yl)ethoxy)phthalonitrile (2) and its soluble aminopyrazole-substituted peripheral metallo (Mn, Co, and Ni)-phthalocyanine complexes (3-5) are reported for the first time. The synthesized compounds and phthalocyanine complexes were characterized spectroscopically. The new phthalonitrile derivative (2) and its peripheral metallophthalocyanine complexes (3-5) were found to be effective inhibitors of α-glycosidase, acetylcholinesterase (AChE), human carbonic anhydrase I and II isoforms (hCA I and II), and butyrylcholinesterase (BChE) with Ki values in the range of 1.55 ± 0.47 to 10.85 ± 3.43 nM for α-glycosidase, 8.44 ± 0.32 to 21.31 ± 7.91 nM for hCA I, 11.73 ± 2.82 to 31.03 ± 4.81 nM for hCA II, 101.62 ± 26.58 to 326.54 ± 89.67 nM for AChE, and 68.68 ± 11.15 to 109.53 ± 19.55 nM for BChE. This is the first study of peripherally substituted phthalocyanines containing an aminopyrazole group as potential carbonic anhydrase enzyme inhibitor. Also, the antimicrobial activities of the synthesized compounds were evaluated against six microorganisms (four bacteria and two Candida species) using the broth microdilution method. The gram-positive bacteria were detected to be more sensitive than gram-negative bacteria and yeasts in the synthesized compounds.

A convenient synthesis of the muscarinic cholinergic antagonist (R)-[N-methyl-3 H]quinuclidinyl benzilate methiodide.

A useful synthesis of (R)-[N-methyl-3 H]quinuclidinyl benzilate methiodide is described with the product characterized by thin-layer chromatography (TLC), high-performance liquid chromatography (HPLC), tritium nuclear magnetic resonance (NMR), and mass spectrometry (MS). Several methods are provided to purify the radioligand, and its storage and stability are also discussed.

Synthesis, crystal structure and biological evaluation of spectroscopic characterization of Ni(II) and Co(II) complexes with N-salicyloil-N'-maleoil-hydrazine as anticholinergic and antidiabetic agents.

[Ni(C11 H9 N2 O5 )2 (H2 O)2 ]•3(C3 H7 NO) (1) and [Co(C11 H9 N2 O5 )2 (H2 O)2 ]•3(C3 H7 NO) (2) are synthesized and characterized by elemental analysis, FT-IR spectra, magnetic susceptibility, and thermal analysis. In addition, the crystal structure of Ni(II) complex is presented. Both complexes show distorted octahedral geometry. In 1 and 2, metal ions are coordinated by two oxygen atoms of salicylic residue and two nitrogen atoms of maleic amide residue from two ligands, and two oxygen atoms from two water molecules. In this paper, both compounds showed excellent inhibitory effects against human carbonic anhydrase (hCA) isoforms I, and II, α-glycosidase, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE). Compounds 1 and 2 had Ki values of 18.36 ± 4.38 and 26.61 ± 7.54 nM against hCA I and 13.81 ± 3.02 and 29.56 ± 6.52 nM against hCA II, respectively. On the other hand, their Ki values were found to be 487.45 ± 54.18 and 453.81 ± 118.61 nM against AChE and 199.21 ± 50.35 and 409.41 ± 6.86 nM against BChE, respectively.

Novel thymol bearing oxypropanolamine derivatives as potent some metabolic enzyme inhibitors - Their antidiabetic, anticholinergic and antibacterial potentials.

A series of classical and newly synthesized thymol bearing oxypropanolamine compounds were synthesized and characterized. Their in vitro antibacterial activity on A. baumannii, P. aeruginosa, E. coli and S. aureus strains were investigated with agar well diffusion method. The results were compared with commercially available drug active compounds. As well as 3a, 3b and 3c have the most significant antibacterial effect among all the tested compounds; approximately all of them have more antibacterial activity than the reference drugs. These novel thymol bearing oxypropanolamine derivatives were effective inhibitors of the α-glycosidase, cytosolic carbonic anhydrase I and II isoforms (hCA I and II), and acetylcholinesterase enzymes (AChE) with Ki values in the range of 463.85-851.05 µM for α-glycosidase, 1.11-17.34 µM for hCA I, 2.97-17.83 µM for hCA II, and 13.58-31.45 µM for AChE, respectively.

The first asymmetric halogen/metal-exchange reaction: desymmetrization of alcohols with enantiotopic bromoarene substituents.

Desymmetrizations of the prochiral bis(bromoaryl)alcohols 1 and 4 were effected by treatment with iPr2Mg and enantiomerically pure lithium alkoxides. The resulting arylmagnesium compounds were quenched with various electrophiles. The absolute and (if relevant) relative configurations of the resulting products were determined. The best ee/yield combination was obtained for the protonolysis furnishing monobromoalcohol (R)-2 (53 % ee, 51 % yield). The latter was converted into (R)-orphenadrine, an antihistaminic and anticholinergic drug.

3D-QSAR study of 8-azabicyclo[3.2.1] octane analogs antagonists of cholinergic receptor.

3D-QSAR models of Comparative of Molecular Field Analysis (CoMFA) and Comparative of Molecular Similarities Indices Analysis (CoMSIA) of 20 8-azabicyclo[3.2.1] octane (potent muscarinic receptor blocker) was performed. These benztropine analogs were optimized using ligand based alignment method. The conventional ligand-based 3D-QSAR studies were performed based on the low energy conformations employing database alignment rule. The ligand-based model gave q(2) value 0.819 and 0.810 and r(2) value 0.991 and 0.988 for CoMFA and CoMSIA, respectively, and the predictive ability of the model was validated. Results indicate that the CoMFA and CoMSIA models could be reliable model which may be used in the design of novel muscarinic antagonists as leads.

Synthesis of a quaternary bis derivative of imipramine as a novel compound with potential anti-enuretic effect.

OBJECTIVES: Imipramine has been used for over four decades (early reports in 1960s) for the treatment of nocturnal enuresis, although the reason for its effect is not clear. Imipramine is a tertiary amine, which may act both in the periphery and/or pass through the blood-brain barrier (BBB) in unionized form and exhibit a central effect. Since imipramine has anti-cholinergic properties, some believe it may exert its anti-enuretic effect by affecting peripheral cholinergic receptors, i.e. its anti-enuretic effect may be due to peripheral anti-cholinergic properties, whereas others think it can pass through the BBB and interact with central nervous system (CNS) receptors. If the anti-enuretic effect of imipramine is due to its peripheral anti-cholinergic effects, its entrance into the CNS is unnecessary. Therefore, the synthesis of a form of imipramine that can exhibit peripheral anti-cholinergic effects but does not have CNS adverse effects would have a safer drug profile in this case. On the other hand, if the anti-enuretic effect of imipramine is primarily due to its action on the CNS, a form of imipramine that cannot pass through the BBB has no effect on nocturnal enuresis treatment and thus may help to clarify the mechanism of action of imipramine in nocturnal enuresis treatment. METHODS: This article describes the synthesis and evaluation of the anti-cholinergic effect of a new bis derivative of imipramine, which contains two imipramine units in its structure. KEY FINDINGS: The compound exhibited anti-cholinergic activity comparable with that of imipramine on isolated guinea pig ileum. CONCLUSIONS: Being a quaternary ammonium, this compound is not expected to be able to cross the BBB and thus would cause fewer CNS side effects.

Design, synthesis, and insecticidal activity evaluation of novel 4-(N, N-diarylmethylamines)furan-2(5H)-one derivatives as potential acetylcholine receptor insecticides.

BACKGROUND: Flupyradifurone is a member of a novel class of insecticides that possess excellent insecticidal activities. Halogen-containing phenyl groups are important and indispensable structural components of many pesticides. However, replacement of the difluoromethyl group of flupyradifurone with halogen-containing phenyl groups has not been reported. Hence, a series of novel butenolide derivatives containing phenyl groups were synthesized and bioassayed to discover novel compounds with excellent insecticidal activities. RESULTS: Some target molecules exhibited good insecticidal activities against Aphis craccivora. Among the title compounds, 4cc showed the best insecticidal activities with an 50% lethal concentration (LC50 ) value of 1.72 µg mL-1 , which is superior to that of pymetrozine (LC50  = 6.86 µg mL-1 ). Molecular docking indicated that 4cc lacks oxidative metabolism by CYP6CM1 and metabolic resistance with imidacloprid. Furthermore, label-free quantitative proteomic analysis indicated that 4cc may be a potential acetylcholine receptor insecticide that acts on the nicotinic acetylcholine receptor. Compound 4cc also decreased the capability for oxidative metabolism, which further supported the molecular docking results. CONCLUSION: This work can be used to further investigate the mechanism underlying the insecticidal activity of butenolide derivatives and develop potential novel butenolide insecticides. © 2018 Society of Chemical Industry.

Polymer-based open-channel blockers for the acetylcholine receptor: the effect of spacer length on blockade kinetics.

Blocking open ion channels provides a promising way to modulate synaptic transmission. Using the muscle-type acetylcholine receptor (AChR) as a test system, we seek to develop blockers that have blockade kinetics tunable via structural modifications. Here we investigate whether the blockade kinetics can be modulated by specifying the length of a poly(ethylene glycol) (PEG) spacer incorporated into the blocker. Single-channel electrophysiological experiments show that simple bis(trimethylammonium) compounds ( 1a- 3) both activate the AChR and block the open channel. The blockade kinetics are found to depend on spacer length: both the association and dissociation rate constants decrease with increasing spacer length. The decrease in the association rate constant can be quantitatively explained by the entropic cost of polymer confinement in the transmembrane lumen, while the decrease in the dissociation rate constant is consistent with weak, additive noncovalent interactions between the channel and the spacer. These results provide useful insights into the future design of kinetically tunable open-channel blockers for the AChR.

Stereoisomers of N-substituted soft anticholinergics and their zwitterionic metabolite based on glycopyrrolate--syntheses and pharmacological evaluations.

PURPOSE: In this study, isomers of two N-substituted soft anticholinergics based on glycopyrrolate, SGM (PcPOAGP_NA.Me) and SGE (PcPOAGP_NA.Et) [3'-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1'-methyl-1'-alkoxycarbonylpyrrolidinium bromide] and their zwitterionic metabolite, SGa (PcPOAGP_NA.H) [3'-(2-cyclopentyl-2-phenyl-2-hydroxyacetoxy)-1'-methyl-1'-carboxymethylpyrrolidinium inner salt] were synthesized and their pharmacological activities were evaluated in vitro and in vivo. METHODS: The isomers of SGM and SGE were synthesized with both optically pure methyl-cyclopentylmandelate and 3-hydroxy-N-methylpyrrolidine. Trans-esterification followed by quarternization with alkyl bromoacetate gave four isomers of SGM or SGE with the nitrogen chiral center unresolved (2R3'S-SGM, 2R3'R-SGM, 2S3'S-SGM, 2S3'R-SGM or 2R3'S-SGE, 2R3'R-SGE, 2S3'S-SGE, 2S3'R-SGE). The hydrolysis of these four isomers followed by HPLC separation resulted in eight fully resolved isomers of SGa (2R3'R1'R, 2R3'S1'R, 2R3'R1'S, 2R3'S1'S, 2S3'R1'R, 2S3'S1'R, 2S3'R1'S, and 2S3'S1'S). Pharmacological activities were assessed by using in vitro receptor-binding assay and guinea pig ileum pA2-assay, and by evaluating the in vivo rabbit mydriatic effects. Results were compared to those obtained with conventional anticholinergic agents, such as glycopyrrolate, N-meythylscopolamine, and tropicamide, as well as those obtained with previously prepared racemic mixtures and 2R isomers. RESULTS: Receptor binding pKi values at cloned human muscarinic receptors (M1-M4 subtypes) were in the 6.0-9.5 range for the newly synthesized SGM and SGE isomers, and in the 5.0-8.6 range for the SGa isomers. In all cases, 2R isomers were significantly more active than 2S isomers (27 to 447 times for SGM isomers, and 6 to 4467 times for SGa isomers). Among the four SGM isomers with unresolved 1' (N) chiral center, the 3'R isomers were more active than the corresponding 3'S isomers (1.5-12.9 times), whereas, among the SGa isomers, the 3'S isomers were not always more active than the corresponding 3'R isomers indicating that activity determined based on configuration at chiral center 3' is significantly affected by the configuration of the other two chiral centers, 2 and 1'. Among the completely resolved eight SGa isomers (all three chiral centers resolved), 1'S isomers were always more active than the corresponding 1'R isomers (1.8-22.4 times). Results also indicate that some isomers showed good M3/M2 muscarinic-receptor subtype-selectivity (about 3-5 times), and 2R and 3'S were the determining configurations for this property. Guinea pig ileum assays and rabbit mydriasis tests on SGa isomers further confirmed the stereospecificity. In rabbit eyes, some 2R-SGa isomers showed mydriatic potencies similar to glycopyrrolate and exceeded tropicamide, but their mydriatic effects lasted considerably shorter, and they did not induce dilation of the pupil in the contralateral, water-treated eye. These results indicate that these compounds are locally active, but safe and have a low potential to cause systemic side effects. The pharmacological potency of the eight SGa isomers was estimated as 2R3'S1'S approximately equal to 2R3'R1'S approximately equal to 2R3'S1'R > 2R3'R1'R > 2S3'R1'S > 2S3'S1'S approximately equal to 2S3'R1'R > 2S3'S1'R (p < 0.05). CONCLUSIONS: The stereospecificity and M3/M2 muscarinic-receptor subtype-selectivity of soft anticholinergics, SGM, SGE, and SGa have been demonstrated. In agreement with previous results, the potential for their effective and safe use has been confirmed.

An efficient approach to the asymmetric total synthesis of (-)-anisodine.

-Anisodine (l-6,7-epoxy-3-tropyl-alpha-hydroxytropate), which was isolated from the medicinal plant Scopolia tanguticus Maxim, was the first efficiently prepared using 6-beta-acetyltropine as the starting material via a key step of the Sharpless asymmetric dihydroxylation (AD). The intermediate compounds 10 and 11 showed promising cholinergic activity.

Preparation and biological effects of pure stereoisomeric novel soft anticholinergics.

A series of pure stereoisomeric soft glycopyrrolate analogues 3, 4 and 5 was synthesized using chiral intermediates and by careful separation of the stereoisomers formed during the last quaternization step of the synthesis. The stereochemistry of the products was elucidated using various 1D and 2D NMR techniques. Anticholinergic activity of the new compounds was determined by receptor binding studies and performing tests on isolated organs and by in vivo tests. Receptor binding revealed that in the higher alkyl ester series the (2R, 1'R, 3'R) and the (2R, 1'S, 3'S) isomers were the compounds showing the highest receptor affinity furthermore it demonstrated the confines of the length of the alkyl chain. In vitro isolated organ experiments correlated well with the receptor binding results, and in vivo investigations indicated the soft character of the compounds.

Synthesis and pharmacological effects of new, N-substituted soft anticholinergics based on glycopyrrolate.

To reduce the possibility of systemic side-effects in locally administered anticholinergics, two new N-substituted glycopyrrolate analogues designed using soft drug design approaches have been synthesized and evaluated in vitro and in vivo. Because stereospecificity is known to be important at muscarinic receptors, the new compounds SGM and SGE also have been prepared as their pure 2R isomers, 2R-SGM and 2R-SGE, by starting from optically pure (-)-cyclopentylmandelic acid, and the corresponding isomers were indeed found to be more active. The new soft glycopyrrolates were chemically more stable under acidic conditions, and the ethyl esters SGE were more stable than the methyl esters SGM. The new compounds were also found to be quite susceptible to extrahepatic metabolism, having half-lives of 20-30 min in rat plasma (in vitro), consistent with their soft nature. Binding studies at human muscarinic receptors (M(1)-M(4)) and guinea-pig ileum assays found 2R-SGM and 2R-SGE to have potencies somewhat less than, but close to, those of glycopyrrolate and N-methylscopolamine. They caused pupil dilation in rabbit eyes, but their mydriatic effects lasted for considerably less time than that of glycopyrrolate, and they did not induce dilation of the pupil in the contralateral, water-treated eyes, indicating that, in agreement with their soft nature, they are locally active, but safe and with a low potential to cause systemic side-effects.