MTEC Research Articles

Characterization of Substituted Phenylpropylamides as Highly Selective Agonists at the Melatonin MT2 Receptor

Melatonin is a widely distributed hormone that regulates several major physiological processes, including the circadian rhythm and seasonal adaptation. The two subtypes of mammalian G protein-coupled melatonin receptors are primarily responsible for mediating the actions of melatonin. Because synthetic melatonin agonists have considerable therapeutic potentials in modulating insomnia and circadian- related sleep disorders, it is highly desirable to develop subtype-selective melatoninergic compounds. The pharmacological potencies of a series of substituted N-[3-(3-methoxyphenyl)propyl] amides towards human melatonin MT(1) and MT(2) receptors were evaluated by the FLIPR high-throughput screening assay, whilst their subtype-selectivity was subsequently verified with ERK phosphorylation and cAMP assays. Structure-activity relationship analysis of highly potent subtype-selective ligands (MT(2) EC(50) 10-90 pM) revealed that a benzyloxyl substituent incorporated at C6 position of the 3-methoxyphenyl ring dramatically enhanced the MT(2) potency and at the same time decreased MT(1) potency. Incorporation of structural moieties conferring the subtype selectivity produced several extremely potent MT(2)-selective ligands. The most potent subtype-selective ligand, 2q had a substantially higher potency for MT(2) receptor than melatonin for elevation of [Ca(2+)]i and inhibition of forskolin-elevated cAMP. Representative MT(2)-selective ligands also induced ERK phosphorylation in both recombinant and native cell lines, and no cross-reactivity to 17 other GPCRs could be detected. These ligands represent invaluable tools for delineating the functional roles of distinct melatonin receptor subtypes and are viable candidates for drug development.

Antihyperglycaemic, antioxidative activities of a formulated polyherbal drug MTEC (Modified) in streptozotocin-induced diabetic rat.

Musa paradisiaca belongs to the family of Musaceae and is distributed throughout India and Malaysia. The plant has medicinal value as antidiabetic agent. Seeds of Tamarindus indica of Caesalpiniaceae family used as traditional medicine for the management of diabetes mellitus found throughout India. Eugenia jambolana an evergreen tree of Myrtaceae family is used as traditional medicine for the management of diabetes in India. Coccinia indica of Cucurbitaceae family is distributed widely all over India and its medicinal value as antidiabetic agent is well recognized. The diabetic therapeutic efficacy of a formulated polyherbal drug (abbreviated form MTEC), constituted with n-hexane fractions of the hydromethanol extract of root of M. paradisiaca, seed of T. indica, seed of E. jambolana and leaf of C. indica at specific ratio was investigated in streptozotocin-induced diabetic rats. Streptozotocin-induced diabetic state was confirmed here by the monitoring of increased level of fasting blood glucose, decreased glycogen level in liver and skeletal muscle along with elevation in the activities of glucose-6phosphatase and lactate dehydrogenase and diminution in the activities of hexokinase as well as glucose-6-phosphate dehydrogenase in liver, skeletal muscle and cardiac muscle. Oral administration of MTEC (modified) at a dose of 100 mg/5 ml of olive oil/Kg body weight daily to the diabetic rats significantly (P<0.05) corrected fasting blood glucose level, glycogen contents of liver and skeletal muscle along with said carbohydrate metabolic enzyme activities in liver, skeletal and cardiac muscles in diabetic rat towards the control levels. Diabetes mellitus induced oxidative stress was also corrected significantly (P<0.05) by the treatment of this polyherbal drug (modified MTEC) to the diabetic rat. Results of the present study support the therapeutic potentiality of this polyherbal drug MTEC for the management of diabetes.