ABSTRACT
The synthesis and glucosidase inhibitory activities of two C-3'- and C-5'-ß-maltose-extended analogues of the naturally occurring sulfonium-ion inhibitor, de-O-sulfonated ponkoranol, are described. The compounds are designed to test the specificity towards four intestinal glycoside hydrolase family 31 (GH31) enzyme activities, responsible for the hydrolysis of terminal starch products and sugars into glucose, in humans. The target sulfonium-ion compounds were synthesized by means of nucleophilic attack of benzyl protected 1,4-anhydro-4-thio-D-arabinitol at the C-6 position of 6-O-trifluoromethanesulfonyl trisaccharides as alkylating agents. The alkylating agents were synthesized from D-glucose by glycosylation at C-4 or C-2 with maltosyl trichloroacetimidate. Deprotection of the coupled products by using a two-step sequence, followed by reduction afforded the final compounds. Evaluation of the target compounds for inhibition of the four glucosidase activities indicated that selective inhibition of one enzyme over the others is possible.
Subject(s)
Intestinal Mucosa/metabolism , Intestines/enzymology , Maltose/antagonists & inhibitors , Maltose/chemistry , Maltose/chemical synthesis , Starch/chemistry , Sucrase-Isomaltase Complex/antagonists & inhibitors , Sucrase-Isomaltase Complex/metabolism , Sulfonium Compounds/antagonists & inhibitors , Sulfonium Compounds/chemistry , Thiophenes/antagonists & inhibitors , Thiophenes/chemical synthesis , alpha-Glucosidases/chemistry , alpha-Glucosidases/chemical synthesis , Catalysis , Enzyme Inhibitors/pharmacology , Humans , Molecular Structure , Stereoisomerism , Thiophenes/chemistryABSTRACT
Trimethylsulfonium, a compound present in the midgut gland of the sea hare Aplysia brasiliana, negatively modulates vagal response, indicating a probable ability to inhibit cholinergic responses. In the present study, the pharmacological profile of trimethylsulfonium was characterized on muscarinic and nicotinic acetylcholine receptors. In rat jejunum the contractile response induced by trimethylsulfonium (pD2 = 2.46 +/- 0.12 and maximal response = 2.14 +/- 0.32 g) was not antagonized competitively by atropine. The maximal response (Emax) to trimethylsulfonium was diminished in the presence of increasing doses of atropine (P<0.05), suggesting that trimethylsulfonium-induced contraction was not related to muscarinic stimulation, but might be caused by acetylcholine release due to presynaptic stimulation. Trimethylsulfonium displaced [3H]-quinuclidinyl benzilate from rat cortex membranes with a low affinity (Ki = 0.5 mM). Furthermore, it caused contraction of frog rectus abdominis muscles (pD2 = 2.70 +/- 0.06 and Emax = 4.16 +/- 0.9 g), which was competitively antagonized by d-tubocurarine (1, 3 or 10 microM) with a pA2 of 5.79, suggesting a positive interaction with nicotinic receptors. In fact, trimethylsulfonium displaced [3H]-nicotine from rat diaphragm muscle membranes with a Ki of 27.1 microM. These results suggest that trimethylsulfonium acts as an agonist on nicotinic receptors, and thus contracts frog skeletal rectus abdominis muscle and rat jejunum smooth muscle via stimulation of postjunctional and neuronal prejunctional nicotinic cholinoreceptors, respectively.
Subject(s)
Aplysia/chemistry , Cholinergic Agents/pharmacology , Nicotinic Agonists/pharmacology , Receptors, Muscarinic/drug effects , Receptors, Nicotinic/drug effects , Sulfonium Compounds/pharmacology , Animals , Atropine/pharmacology , Dose-Response Relationship, Drug , Male , Muscle Contraction/drug effects , Rats , Rats, Wistar , Sulfonium Compounds/antagonists & inhibitorsABSTRACT
In the presence of tripropylsulfonium bromide (TPS) (1 X 10(-4) g/ml), a new compound, the phasic contraction of the isolated guinea pig ileum to 5-hydroxytryptamine (5-HT) (5 X 10(-7) g/ml) was consistently enhanced ("TPS effect"). TPS alone increased moderatley the spontaneous movement of the ileum. When the contraction height was calculated as the percentage of that to 5-HT alone, such was observed in the "TPS effect" to be 167.1 +/- 3.6% (mean +/- S.E., n = 80). TPS did not enhance the contraction due to acetylcholine or histamine. The "TPS effect" remained unaffected in the presence of dibenzyline (1 X 10(-7) g/ml), was abolished by morphine(1 X 10(-6) g/ml), tetrodotoxin (2 X 10(-8) g/ml) adenosine (3 X 10(-6) g/ml) and atropine (1 X 10(-7) g/ml) and was not observed under anoxic conditions. Eserine (1 X 10(-8) g/ml) strengthened the "TPS effect" markedly. It is concluded that this effect may be the result of the potentiating effect of TPS on the action of 5-HT through the M receptors, possibly by the facilitation of the acetylcholine-liberation from the nervous tissue.
