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1.
J Pharm Sci ; 76(2): 149-52, 1987 Feb.
Article in English | MEDLINE | ID: mdl-3106615

ABSTRACT

A number of N-benzenesulfonylglycines, alanines, sarcosine, and prolines, which contain the minimum pharmacophore moieties necessary for aldose reductase inhibitory activity, were prepared and tested in the rat lens assay. In this assay, the benzenesulfonylglycines are considerably more potent than the corresponding alanine and sarcosine derivatives which, in turn, are more active than the proline analogues. Of the monosubstituted benzenesulfonylglycines, the 2-nitro and 4-amino derivatives were most active with 50% inhibitory concentration (IC50) values of 13 and 16 microM, respectively. The most potent derivatives evaluated were the beta- and alpha-naphthylenesulfonylglycines with IC50 values of 0.4 and 1.3 microM, respectively. The structure-activity data obtained from evaluation of the benzenesulfonylamino acids suggests that the aromatic ring and ring substituents, as well as the sulfonamide group and carboxylate moiety, all contribute to the inhibitory potency through direct interaction with complimentary binding sites present on aldose reductase.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Benzenesulfonates/pharmacology , Sugar Alcohol Dehydrogenases/antagonists & inhibitors , Amino Acids , Animals , Benzenesulfonates/chemical synthesis , In Vitro Techniques , Lens, Crystalline/enzymology , Rats , Structure-Activity Relationship
2.
J Med Chem ; 29(10): 2024-8, 1986 Oct.
Article in English | MEDLINE | ID: mdl-3093680

ABSTRACT

A number of 2-oxoquinoline-1-alkanoic acids that contain the N-acylglycine fragment found in several known inhibitors of aldose reductase were synthesized and tested in the rat lens assay. All of the target compounds were prepared by alkylation of the appropriate 2-oxoquinoline intermediates with a halo ester, followed by hydrolysis of the intermediate esters. In the rat lens assay, the 1-acetic acid derivatives 9a-e display the highest level of aldose reductase inhibitor activity with IC50 values of 0.45-6.0 microM. Modification of the 1-acetic acid moiety by esterification, substitution of an alpha-methyl group, or insertion of an additional methylene unit results in reduced inhibitory potency. Structure-activity data also suggests that both the benzene and 2-oxopyridine rings of 9a-e contribute substantially toward activity and that inhibitory potency is influenced by aromatic ring substituents.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Quinolines/chemical synthesis , Sugar Alcohol Dehydrogenases/antagonists & inhibitors , Animals , Enzyme Inhibitors/chemical synthesis , Quinolines/pharmacology , Rats , Stereoisomerism , Structure-Activity Relationship
3.
J Med Chem ; 29(8): 1528-31, 1986 Aug.
Article in English | MEDLINE | ID: mdl-3735319

ABSTRACT

Three 7-methyl-1,4-dioxa-7-azaspiro[4.5]decanes that contained either the benzyl, 3-indolylmethyl, or 4-indolylmethyl group at the 6-position were synthesized via alkylation of the pyrrolidine enamine of the key intermediate, ethyl 3-oxopiperidine-1-carboxylate. The spirodecane derivatives were evaluated for in vivo central and peripheral dopamine agonist activity. None of the compounds displayed central nervous system activity; however, the 4-indolymethyl analogue exhibited potent dopamine agonist activity in the cat cardioaccelerator nerve assay and possesses an ID50 of 0.095 mumol/kg compared to apomorphine, which possesses an ID50 of 0.0348 mumol/kg in the same assay.


Subject(s)
Dopamine , Indoles/chemical synthesis , Spiro Compounds/chemical synthesis , Alkylation , Animals , Apomorphine/pharmacology , Behavior, Animal/drug effects , Cats , Corpus Striatum/drug effects , Corpus Striatum/metabolism , Heart Rate/drug effects , Indoles/pharmacology , Male , Posture , Pyrrolidines , Rats , Rats, Inbred Strains , Spiperone/metabolism , Spiro Compounds/pharmacology
4.
J Med Chem ; 29(6): 1094-9, 1986 Jun.
Article in English | MEDLINE | ID: mdl-3086557

ABSTRACT

A number of 4,7-disubstituted benzopyran-2-ones were synthesized and evaluated for crude rat lens aldose reductase inhibitory activity. Substituents on position 4 included CH3, CO2H, CH2CO2H, CH = CHCO2H, and CH2CH2CO2H. The aromatic substituents included OH, OCH3, OCOCH3, CH2CH3, and Cl. Also included in the study were 3-oxo-3H-naphtho[2,1-b]pyran-1-acetic, 2-oxo-2H-naphtho[1,2-b]pyran-4-acetic, and 1-naphthylacetic acids. The benzopyran and naphthopyran derivatives were prepared by the classical von Pechmann reaction. General structure-activity relationships reveal that optimal enzyme inhibitory activity is displayed by those compounds possessing the acetic acid moiety. For example, the most potent derivative, 3-oxo-3H-naphtho[2,1-b]pyran-1-acetic acid with an IC50 of 0.020 microM, is as potent as sorbinil (IC50 = 0.017 microM) in the crude rat lens aldose reductase assay.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Benzopyrans/chemical synthesis , Lens, Crystalline/enzymology , Sugar Alcohol Dehydrogenases/antagonists & inhibitors , Animals , Benzopyrans/pharmacology , Kinetics , Rats , Structure-Activity Relationship
5.
J Med Chem ; 29(5): 627-9, 1986 May.
Article in English | MEDLINE | ID: mdl-3084783

ABSTRACT

A number of 2-(arylamino)-4(3H)-quinazolinones (2a-i) that possess several of the pharmacophore moieties necessary for binding to the inhibitor site of the enzyme aldose reductase were synthesized and tested for their ability to inhibit crude aldose reductase obtained from rat lens. Only those quinazolinones that possess an acidic moiety on the 2-(arylamino) substituent were found to display significant inhibitory activity. Of these, the most potent compound is the 4'-CO2H derivative (2i) with an IC50 of 34 microM, while the least potent is the 4'-OH derivative (2c) with an IC50 of 75 microM. All of the 2-(arylamino)-4(3H)-quinazolinones tested are less potent than other known inhibitors of aldose reductase, such as alrestatin and sorbinil, indicating that the pharmacophore moieties present in these compounds may not be positioned optimally relative to one another for maximal interaction with the enzyme.


Subject(s)
Aldehyde Reductase/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Lens, Crystalline/enzymology , Quinazolines/chemical synthesis , Sugar Alcohol Dehydrogenases/antagonists & inhibitors , Animals , Enzyme Inhibitors/pharmacology , Quinazolines/pharmacology , Rats
6.
Brain Res ; 330(1): 135-40, 1985 Mar 18.
Article in English | MEDLINE | ID: mdl-2985189

ABSTRACT

Experiments were undertaken to determine the site of action of securinine and related convulsant indolizidines. All of these compounds induced tonic seizures in mice, with CD50 values ranging from 11 to 87 mg/kg. The CD50 for bicuculline was found to be 8 mg/kg. Equilibrium binding assays revealed that securinine and dihydrosecurinine inhibit [3H]GABA binding to rat brain membranes with an IC50 of approximately 50 microM, which is some 7 times less potent than bicuculline. Allosecurinine and virosecurinine have IC50 values greater than 1 mM. Both dihydrosecurinine and securinine inhibited GABA-stimulated benzodiazepine binding in rat brain membranes, though they were somewhat weaker than bicuculline in this respect. Other binding assays revealed that securinine and its analogs were inactive as inhibitors of bicuculline-insensitive GABA binding, benzodiazepine, cholinergic muscarinic, and beta-adrenergic receptor binding. In addition, while thiocyanate ion increased the apparent binding potency of bicuculline 10-fold, it had little effect on that of securinine. Extracellular electrophysiological studies on neurons in the cat spinal cord indicated that securinine and dihydrosecurinine blocked the inhibitory action of GABA while having no effect on that of glycine. Allo- and virosecurinine were much less active as GABA receptor antagonists in this test. These results suggest that, like bicuculline, securinine and dihydrosecurinine are selective antagonists of GABA recognition sites on mammalian central neurons.


Subject(s)
Alkaloids/pharmacology , Azepines , Central Nervous System/drug effects , Convulsants , Lactones , Piperidines , Receptors, GABA-A/drug effects , Animals , Bicuculline/pharmacology , Cats , Female , Heterocyclic Compounds, 4 or More Rings , Heterocyclic Compounds, Bridged-Ring , Mice , Mice, Inbred ICR , Seizures/chemically induced , Stimulation, Chemical
7.
J Med Chem ; 24(2): 149-53, 1981 Feb.
Article in English | MEDLINE | ID: mdl-7205882

ABSTRACT

Replacement of the catechol 3,4-dihydroxylation pattern of certain adrenergic beta-phenethylamines by a resorcinol 3,5-dihydroxylation pattern has led to a greater selectivity of adrenergic agonist effects in certain molecules. This strategy has been applied to a series of dopaminergic agents derived from 2-aminotetralin, leading to a 5,7-dihydroxylation pattern. Traditional literature approaches to formation of a tetralin ring with this oxygenation pattern failed. A method was used which involved cyclization of 3,5-dimethoxybenzylsuccinic acid derivatives with pyridinium poly(HF) and subsequent modification of the tetralin ring. The resorcinol-derived 2-aminotetralins were less potent and less active dopaminergic agents than their catechol-derived isomers (5,6-dihydroxy and/or 6,7-dihydroxy). Certain of the subject compounds demonstrated alpha- and beta 1-adrenoceptor activating properties.


Subject(s)
Dopamine/physiology , Naphthalenes/chemical synthesis , Sympathomimetics/chemical synthesis , Tetrahydronaphthalenes/chemical synthesis , Animals , Blood Pressure/drug effects , Cats , Chemical Phenomena , Chemistry , Dogs , Female , Guinea Pigs , Heart Rate/drug effects , In Vitro Techniques , Male , Mice , Rats , Receptors, Adrenergic/drug effects , Receptors, Dopamine/drug effects , Tetrahydronaphthalenes/pharmacology
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