E-6837 is an orally active, 5-HT₆ agonist developed in an attempt to create an

anti-obesity medication Anti-obesity medication or weight loss medications are pharmacological agents that reduce or control excess body fat. These medications alter one of the fundamental processes of the human body, weight regulation, by: reducing appetite and con ...

. In cell lines expressing rat 5-HT₆ receptors, it acted as a

partial agonist In pharmacology, partial agonists are drugs that bind to and activate a given Receptor (biochemistry), receptor, but have only partial Intrinsic activity, efficacy at the receptor relative to a full agonist. They may also be considered Ligand (bio ...

(on presumed silent receptors), while it acted as a

full agonist An agonist is a chemical that activates a receptor to produce a biological response. Receptors are cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an antagonist blocks the action of the agoni ...

on human 5-HT₆ receptors (which are constitutively active). Oral administration of E-6837 reduced food intake, but only transiently. In rats, twice daily administration of E-6837 over the course of 4 weeks resulted in a 15.7% reduction in body weight, compared to 11% reduction for sibutramine. This weight loss remained significant for E-6837 after a 43-day withdrawal period, whereas the weight difference was non-significant for sibutramine (i.e., sibutramine had a

rebound effect The rebound effect, or rebound phenomenon, is the emergence or re-emergence of symptoms that were either absent or controlled while taking a medication, but appear when that same medication is discontinued or reduced in dosage. In the case of re- ...

while E-6837 did not), and this weight loss was found to be due to a loss of fat mass. The reduction in fat mass in E-6837 treated animals was associated with a 50% decrease in plasma

leptin Leptin (from Ancient Greek, Greek λεπτός ''leptos'', "thin" or "light" or "small"), also known as obese protein, is a protein hormone predominantly made by adipocytes (cells of adipose tissue). Its primary role is likely to regulate long ...

levels, and also reduced glucose and

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the insulin (''INS)'' gene. It is the main Anabolism, anabolic hormone of the body. It regulates the metabol ...

levels in plasma after a

glucose tolerance test The glucose tolerance test (GTT, not to be confused with GGT test) is a medical test in which glucose is given and blood samples taken afterward to determine how quickly it is cleared from the blood. The test is usually used to test for diabetes, ...

. This indicates that weight loss from E-6837 is associated with improved insulin sensitivity, and thus, better

glycemic control Diabetes mellitus is a metabolic disease that is characterized by chronic elevated blood glucose levels (hyperglycemia). Therefore, the main goal of diabetes management is to keep blood glucose levels within normal limits or a target range as ...

. One proposed mechanism of action is that E-6837 acts on neurons in the hypothalamus, which has shown significant levels of 5-HT₆ receptor mRNA. The hypothalamus is one key structure involved in regulating food intake.

References

{{Tryptamines 5-HT6 agonists Anorectics Chloroarenes N,N-Dialkyltryptamines Naphthalenes

See also

References