BI 456906: Discovery and preclinical pharmacology of a novel GCGR/GLP-1R dual agonist with robust anti-obesity efficacy.

Objective: Obesity and its associated comorbidities represent a global health challenge with a need for well-tolerated, effective, and mechanistically diverse pharmaceutical interventions. Oxyntomodulin is a gut peptide that activates the glucagon receptor (GCGR) and glucagon-like peptide-1 receptor (GLP-1R) and reduces bodyweight by increasing energy expenditure and reducing energy intake in humans. Here we describe the pharmacological profile of the novel glucagon receptor (GCGR)/GLP-1 receptor (GLP-1R) dual agonist BI 456906.

Effects of GPR139 agonism on effort expenditure for food reward in rodent models: Evidence for pro-motivational actions.

Apathy, deficiency of motivation including willingness to exert effort for reward, is a common symptom in many psychiatric and neurological disorders, including depression and schizophrenia. Despite improved understanding of the neurocircuitry and neurochemistry underlying normal and deficient motivation, there is still no approved pharmacological treatment for such a deficiency. GPR139 is an orphan G protein-coupled receptor expressed in brain regions which contribute to the neural circuitry that controls motivation including effortful responding for reward, typically sweet gustatory reward.

The calcitonin receptor is the main mediator of LAAMA's body weight lowering effects in male mice.

The anorectic action of the pancreatic hormone amylin is mainly mediated through the area postrema (AP). Amylin activates AP neurons using a heterodimeric receptor (AMY) composed of the calcitonin receptor (CTR) and the receptor activity modifying protein (RAMP 1, 2 or 3). The aim of the following experiments is to test the effects of the long acting amylin analogue (LAAMA) in RAMP1/3 knock-out (KO) male mice and in neuronal CTR KO Nestin-Cre male mice.

The long-acting amylin/calcitonin receptor agonist ZP5461 suppresses food intake and body weight in male rats.

The peptide hormone amylin reduces food intake and body weight and is an attractive candidate target for novel pharmacotherapies to treat obesity. However, the short half-life of native amylin and amylin analogs like pramlintide limits these compounds' potential utility in promoting sustained negative energy balance. Here, we evaluate the ability of the novel long-acting amylin/calcitonin receptor agonist ZP5461 to reduce feeding and body weight in rats, and also test the role of calcitonin receptors (CTRs) in the dorsal vagal complex (DVC) of the hindbrain in the energy balance effects of chronic ZP5461 administration.

Characterization of combined linagliptin and Y2R agonist treatment in diet-induced obese mice.

Dipeptidyl peptidase IV (DPP-IV) inhibitors improve glycemic control by prolonging the action of glucagon-like peptide-1 (GLP-1). In contrast to GLP-1 analogues, DPP-IV inhibitors are weight-neutral. DPP-IV cleavage of PYY and NPY gives rise to PYY and NPY which exert potent anorectic action by stimulating Y2 receptor (Y2R) function.

SGLT6 - A pharmacological target for the treatment of obesity?

Despite increased knowledge of nutrient intake regulation and energy homeostasis, treatment options for obesity remain limited. Food reward consists of two branches: gustatory and post-ingestive nutritive information. Drosophila lacking dSLC5A11 (sodium/glucose cotransporter 6-SGLT6) prefer L-glucose over D-glucose independently of their state of satiety.

Modeling energy intake and body weight effects of a long-acting amylin analogue.

The inhibitory effect of anti-obesity drugs on energy intake (EI) is counter-acted by feedback regulation of the appetite control circuit leading to drug tolerance. This complicates the design and interpretation of EI studies in rodents that are used for anti-obesity drug development. Here, we investigated a synthetic long-acting analogue of the appetite-suppressing peptide hormone amylin (LAMY) in lean and diet-induced obese (DIO) rats.