Derivatives of 3-Pyrrolidinols--III. The Chemistry, Pharmacology, and Toxicology of some N-Substituted-3-Pyrrolidyl α-Substitutes Phenylacetates

Franko, Bernard V.; Lunsford, Carl D.

doi:10.1021/jm50012a004

Cited by 43 publications

(18 citation statements)

References 5 publications

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“…The new soft glycopyrrolate analogues, SGM and SGE (cyclopentylphenylhydroxyacetoxy-1-methyl-1-(alkoxy-carbonyl)pyrrolidinium bromide; alkoxy-being methoxyand ethoxy-for SGM and SGE, respectively), were synthesized as shown in Figure 1 except for the second, resolution step. This involved (i) Grignard reaction of cyclopentylmagnesium bromide with benzoylformic acid in anhydrous ether to give the racemic cyclopentylmandelic acid 1; (ii) methylation of 1 with methyl iodide and potassium carbonate in DMF at room temperature to yield methyl cyclopentylmandelate 2; (iii) transesterification (Franko & Lunsford 1960) of 2 with 1-methyl-3pyrrolidinol (3) in heptane to give N-methyl-3-pyrrolidinyl cyclopentylmandelate 4; and (iv) quaternization of 4 with alkyl bromoacetate in acetonitrile to give the final product 5 (SGM and SGE). These are racemic soft glycopyrrolate analogues, and they were characterized by NMR and elemental analysis.…”

Section: Synthesismentioning

confidence: 99%

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

Dai

et al. 2005

Journal of Pharmacy and Pharmacology

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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.

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Section: Synthesismentioning

confidence: 99%

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

Dai

et al. 2005

Journal of Pharmacy and Pharmacology

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“…While investigating a number of pyrrolidinol derivatives Franko & Lunsford (1960) found glycopyrronium bromide (Glycopyrrolate USNF) to be a potent anticholinergic agent. This is a water soluble quaternary ammonium compound ( Figure 1) with a molecular weight of 398.34.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the anticholinergic actions of glycopyrronium bromide.

Mirakhur¹,

Dundee²,

Jones³

1978

Brit J Clinical Pharma

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1. Glycopyrronium was evaluated by intramuscular, intravenous and oral routes in six adult volunteers for its efficacy as an antisialogogue as also for its action on other aspects of cholinergic activity. 2. It was found to be an effective antisialogogue of long duration of action by all three routes. When given orally the effects were delayed in onset and persisted for too long. Intramuscular and intravenous routes were useful. The intramuscular absorption of the drug is rapid and consistent. 3. Sweat gland activity was affected in a similar fashion but less consistently and other parameters were mostly unaffected. 4. Glycopyrronium 0.2 mg intramuscularly was found to be the optimal dose. Larger doses produced subjective discomfort out of proportion to a further reduction in salivary secretion. 5. Intravenous administration causes no changes in cardiovascular stability.

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“…In the dosage used in the present study (1 mg. of glycopyrrolate 4 times a day), no side effects were encountered. (1) Glycopyrrolate was found to be an effective antisecretory agent.…”

Section: Resultsmentioning

confidence: 99%

Physiological Effects and Clinical Evaluation of Glycopyrrolate in Peptic Ulcer Disease

Moêller

1962

Annals of the New York Academy of Sciences

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Derivatives of 3-Pyrrolidinols--III. The Chemistry, Pharmacology, and Toxicology of some N-Substituted-3-Pyrrolidyl α-Substitutes Phenylacetates

Cited by 43 publications

References 5 publications

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

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

Evaluation of the anticholinergic actions of glycopyrronium bromide.

Physiological Effects and Clinical Evaluation of Glycopyrrolate in Peptic Ulcer Disease

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