It describes various receptor that are responsible for controlling obesity. So new drug targets of obesity is best described

1. NEWER
DRUG
TARGETS
FOR
OBESITY
SIDDHARTH NARUKA
NIDHI SHAH

2. INTRODUCTION
 OBESITY IS A CHRONIC , MULTIFACTORIAL DISEASE CHARACTERIZED BY AN EXCESSIVE ACCUMULATION
OF ADIPOSE TISSUE.
 OBESITY LEADS TO VARIOUS OTHER DISEASES LIKE CARDIOVASCULAR DISEASE, DIABETES , FATTY LIVER
DISEASE , KIDNEY DISEASE AND CERTAIN TYPES OF STROCK.

3. CLASSIFICATION
 The available drugs were not as efficacious as desired
 Thus the need for developing new drugs and targets
has arised.

4. NEWER DRUG TARGETS FOR OESITY
1. LEPTIN AND AMYLIN
• LEPTIN IS A PROTEIN PRIMARILY SECRETED FROM THE ADIPOSE TISSUE. IT DIRECTLY STIMULATES THE ANOREXIGENIC POMC NEURONS AND INHIBITS THE OREXIGENIC NPY NEURONS IN THE HYPOTHALAMUS,
THUS PROMOTING SATIETY AND WEIGHT LOSS.
• HIGH AMOUNT OF LEPTIN CAUSES LEPTIN RESISTANCE IN OBESE PERSON BUT BY INCREASING DOSE OF LEPTIN RESISTANCE CAN BE OVERCOME.
• AMYLIN IS A 37-AMINO ACID NEUROENDOCRINE PEPTIDE HORMONE COSECRETED POSTPRANDIALLY WITH INSULIN BY PANCREATIC Β-CELLS
• AMYLIN EXERTS CENTRALLY MEDIATED GLUCOREGULATORY AND ANOREXIGENIC ACTIONS BY INHIBITING GASTRIC EMPTYING AND GLUCAGON SECRETION AS WELL AS DECREASING MEAL SIZE AND CALORIE
INTAKE (FAT SPECIFIC) IN A DOSE-DEPENDENT MANNER.
• COMBINATION OF LEPTIN/PRAMLINTIDE WAS IN DEVELOPING STAGE BUT IT WAS STOPPED BY THEIR DEVELOPERS.
• THESE COMBINATION SHOWED REDUCED BODY WEIGHT ON AVERAGE BY 12.7%, SIGNIFICANTLY MORE THAN TREATMENT WITH PRAMLINTIDE ALONE (8.4%)
2 SELECTIVE SEROTONIN RECEPTOR AGONIST
• THE SEROTONIN (5-HT) SYSTEM DIRECTLY MODULATES THE HYPOTHALAMIC POMC (ANOREXIGENIC) AND NPY (OREXIGENIC) NETWORKS, ENHANCING SATIETY AND CAUSING HYPOPHAGIA.
• THESE EFFECTS ARE MEDIATED BY 5-HT2C AND 5-HT1B RECEPTORS, LOCATED ON HYPOTHALAMIC POMC AND NPY NEURONS, RESPECTIVELY. THROUGH THE 5-HT1B RECEPTORS, SEROTONIN
INHIBITS THE NPY/AGRP NEURONS, WHILE THROUGH THE 5-HT2C RECEPTORS IT DIRECTLY ACTIVATES THE ANOREXIGENIC POMC NEURONS.
• COMBINATION OF BUPROPION/ NALTREXONE IS APPROVED BY FDA IN 2014 FOR BODY WEIGHT MANAGEMENT IN PEOPLE WHO ARE OBESE.
• COMBINATION OF BUPROPION/ZONISAMIDE IS CURRENTLY IN PHASE 3 CLINICAL TRIALS. ZONISAMIDE IS AN ANTIEPILEPTIC DRUG. IT GIVES ANTIOBESITY ACTIVITY BY ACTING AS
SELECTIVE SEROTONIN AGONIST AND DOPAMINE REUPTAKE INHIBITOR
• IN 2012, FDA APPROVED PHENTEREMINE/TOPIRAMATE ER COMBINATION FOR REDUCING CALORIC DIET.

5. 3 NEUROPEPTIDE Y INHIBITORS
• THE ARC NPY NEURONS INHIBIT THE ANOREXIGENIC POMC NEURONS (VIA NPY Y1 AND Y5 RECEPTORS) AND PROMOTE THE RELEASE OF
THE OREXIGENIC NEUROPEPTIDES OREXIN AND MCH IN THE LHA, THUS PROMOTING FOOD INTAKE. THEREFORE, NPY BLOCKADE COULD
BE A PROMISING TARGET FOR BODY WEIGHT MANAGEMENT.
• ANIMAL EXPERIMENTS (IN MICE) HAVE SHOWN THAT PHARMACOLOGIC BLOCKADE OR GENETIC DELETION OF THE Y1- AND Y5-
RECEPTORS REDUCES FOOD INTAKE AND WEIGHT, WITH Y1-RECEPTOR SIGNALING APPEARING TO BE THE MAJOR MEDIATOR OF THE
OREXIGENIC EFFECTS OF NPY.
• HOWEVER, NPY IS THE MOST ABUNDANT CENTRAL NEUROPEPTIDE AND REGULATES MANY FUNCTIONS BEYOND FEEDING; THUS,
TARGETING NPY NEURONS/Y RECEPTORS SPECIFICALLY FOR OBESITY IS NOT EASY AND COULD RESULT IN UNACCEPTABLE SIDE
EFFECTS.
• THE COMBINED Y1/Y5-RECEPTOR ANTAGONISM MAY PROVE MORE EFFECTIVE, THOUGH WE ARE NOT AWARE OF ANY Y1/Y5-RECEPTOR
ANTAGONIST IN DEVELOPMENT TO DATE.
• IN CONTRAST TO Y1 AND Y5, THE Y2- AND Y4-RECEPTORS ARE THE TARGETS OF THE SATIETY HORMONES PYY AND PANCREATIC
POLYPEPTIDE (PP), RESPECTIVELY, AND, AS MENTIONED BELOW, TWO DRUGS, A Y2/Y4-RECEPTOR AGONIST (OBINEPITIDE AND A
SELECTIVE Y4-RECEPTOR AGONIST (TM30339;), ARE IN PHASE I/II CLINICAL TRIALS AND ARE YIELDING RESULTS THAT APPEAR QUITE
PROMISING AS REGARDS WEIGHT LOSS.

6. GLUCAGON LIKE PEPTIDE
 Glucagon like peptide produce satiety by acting on hind brain region of hypothalamus and other autonomic control area
 Glp -1(bio active form glp17-36, glp 17-37 ) had short duration of action due to cleaved by dpp4 So glp 1 analogue has invented to increase
duration of action
 Glp 1 receptor( glp1-r) is principle mediator of anorectic effect which is expressed by Gut, pancreas, hypothalamus, and vagal afferent nerves.
 There are various glp-1 analogue are used in clinical trials like Exenatide, lixisenatide, liraglutide, taspoglutide, albiglutide, ly2189264, CJC -
1134- PC in which liraglutide is approved by FDA
 There are several combination of GLP- 1 analogue (2 mg) and PYY 3 - 36 (1 mg) enhanced fullness at meal on set and induce significant
reduction at energy intake.
OXYNTOMODULIN (OXM)
 Oxyntomodulin ( OXM) an anorexigenic peptide hormone which act by activating neuron in hypothalamus
 Combined therapy of OXM and PYY3 - 36 is more efficacious than mono therapy of both which act in gastric emptying time,
glucose metabolism and energy intake.
 OXM is short acting and major component is cleaved by DPP -4 so, structuraly modified analogue has made which are long
acting like TKS1225, OXY -RPEG
Lower intestinal satiety

7. GHRELIN INHIBITORS
 Ghrelin is an orexigenic hormone which powerfully enhances NPY orexigenic signalling
 So there are new approaches for drug which block GOAT (ghrelin o acetyltransferase) an enzyme.
FAT SPECIFIC SATIATION PEPTIDE
 Enterostatin administration decreases dietary fat intake in animals but not effective in human as animaL
 Apolipoprotein A- 4 act as satiety factor which is Downregulated by leptin and unregulated by PYY and insulin
 Although administration of apo A-4 quite effective concerning meal size, food intake weight gain reduction in rats but we still
lack data regarding apo A-4 in human.
PERIPHERAL MODULATORS
 Beta agonist activate beta adrenergic receptors which expressed in Adipocytes and cause Lipolysis, thermogenesis There is
clinical trial of L- 796568 which is failed due to minimal level of B- Adrenoreceptors in white adipose tissue and brown
adipose tissue.
 So now a days there is combination of B-3 agonist LY - 377604 and sibutramine in phase -2 clinical trial which shows weight
loss in men and women.
ENTEROSTATIN & APOLIPOPROTEIN
BETA 3 ADRENORECEPTOR AGONIST

8. • 11 BETA HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITORS
11Bhsd enhance conversion of inactive cortisone to active cortisol
Bhsd1 enhance conversion of inactive cortisone to active cortisol which is crucial for pathogenesis of
obesity and metabolic syndrome like insulin resistance
So, evaluation11Bhds1 inhibitors like carbenoxolone and T-BVT which gives anti -obesity effect
ANGIOGENESIS INHIBITOR
 Expansion of adipose tissue by vascular growth factor like vascular endothelial growth factor (VEGF) , hepatocyte growth
factor (HGF) , angiogenin occur
 There are several naturally occurring angiogenesis inhibitors like green tea, garlic, gingseng,etc but not clinical trail, there is
ALS- L1023 in phase -2 clinical trial as anti-angiogenic.
SIRTULIN 1 ACTIVATORS
 Role of cyclic gmp signalling in anti -obesity pharmacotherapy 3-5 cyclic gmp and 3-5 cyclic amp are second messengers
important in biological process 3-5 cyclic AMP activatw AMPK signalling.
 Activation of AMPK facilitates fatty acid oxidation , promote energy expenditure, in hypothalamus promotes food intake
behaviour
 Medication targeting cyclic GMP pathway with FDA, EMA approved drugs such as sildenafil, linaclotide.

9. CONCLUSION
The FDA recently approved three anti-obesity drugs, of which two are combinations of two different
agents that target different regulators of the appetite/feeding system. Data from bariatric surgery
weight loss and subsequent eating behaviour modulations suggest that the mechanisms of long-
term weight loss following bariatric surgery are insufficient to account for the resulting body weight
loss alone (207-209) and that alteration of previously described gut hormones and neuroendocrine
signaling may be actively involved in postoperative changes in eating behavior and appetite (210,
211).
 In addition, a shift away from pharmacological agents that act on pathways in the CNS could lead
to drugs with fewer side effects and more favorable risk/benefit ratios. Therefore, pharmacological
intervention for the management of obesity in the future will most likely be a combination of the
above neuropeptides in a manner that mimics the changes underlying the surgically induced weight
loss