Figure 2. Molecular targets for anti-obesity pharmacotherapeutics.

(2a) Phentermine stimulates the release of dopamine (DA) into the synapse from the presynaptic dopaminergic neurons from the ventral tegmental area (VTA). This released dopamine binds and activates dopamine receptors, including D1 and D2, on postsynaptic neurons in the nucleus accumbens. Dopamine is taken back up into the presynaptic neuron by the dopamine transporter (DAT), which is bound and inhibited by bupropion. Pramlintide and davalintide are amylin analogs that activate amylin receptors (CTR) in the dorsal vagal complex (DVC). Exenatide, liraglutide, and NN9924 are GLP-1 analogs that activate GLP-1 receptors (GLP-1R) in the hypothalamus and DVC. S-2367 binds and inhibits Y5 receptors in the hypothalamic paraventricular nucleus (PVN) to suppress neuropeptide Y (NPY) signaling. RM493 is a melanocortin 4 receptor (MC4R) agonist that binds and activates MC4R in the PVN and lateral hypothalamic area (LHA). Topiramate induces gamma-aminobutyric acid (GABA) receptor-mediated inhibitory currents. TKS1225 and OXY-RPEG are oxyntomodulin (OXM) analogs that bind and activate GLP-1R in the arcuate nucleus and DVC. Lorcaserin selectively binds and activates 5-HT2c serotonin receptors in the arcuate nucleus. Symbols: blue receptor = activating; red receptor = inhibiting. (2b) Topiramate's exact mechanism of action is unknown, but may involve its ability to block voltage-gated sodium channels in the presynaptic excitatory neuron; antagonize AMPA/NMDA glutamate receptors on postsynaptic neurons; and enhance the activity of inhibitory GABA neurons. (2c) Orlistat binds and inhibits gastric and pancreatic lipases in the intestine. These lipases hydrolyze dietary triglycerides into free fatty acids that can be absorbed by intestinal epithelial cells via fatty acid transporters. Thus, orlistat suppresses systemic lipid absorption.