TABLE 2.

List of antiobesity drugs

Drug	Target	Mechanism of action	Usage	Side‐effects	Clinical status	Reference
Section I
Setmelanotide	MC4R	Decreased food intake and increased energy expenditure via MC4R binding	LT	Reported safe	Approved	36, 108
PL‐8905	MC4R	‐do‐*	—	Reported safe	Clinical studies	49
LY2112688	MC4R	‐do‐	—	Increased systolic blood pressure	Failed in clinical studies	26, 105
Melanotan‐II	MC4R	‐do‐	—	Spontaneous penile erection; skin darkening	Failed for obesity	49, 106
Bremelanotide	MC4R	‐do‐	—	Increase blood pressure and sexual activity	Failed for obesity	49, 107
4‐PBA	MC4R	Acts as chemical chaperone and helps rescue intracellular retention of variant MC4Rs	—	Lacks specificity	Preclinical	69, 70, 71
UBE‐41	MC4R	‐do‐	—	Lacks specificity	Preclinical	70, 71
THIQ	MC4R	Acts as pharmacological chaperone and helps rescuing intracellular retention of variant MC4Rs	—	Prolonged exposure decreases cell surface expression and signalling	Preclinical	75
NBP	MC4R	‐do‐	—	‐do‐	Preclinical	72
ML00253764	MC4R	‐do‐	—	High EC50	Preclinical	69, 72
DCPMP	MC4R	‐do‐	—	High EC50	Preclinical	69, 72
Ipsen 5i	MC4R	‐do‐	—	Reported efficient	Preclinical	75
Ipsen 17	MC4R	‐do‐	—	Reported efficient	Preclinical	73
Section II
Orlistat	Pancreatic/stomach lipases	Decreases fat absorption	LT	Abdominal pain, diarrhea	Approved	114
Liraglutide	GLP‐1R	Centrally (CNS) mediated	LT	Adverse GI effects	Approved	115, 116
Semaglutide	GLP‐1R	‐do‐	LT	‐do‐	Approved	117
Naltrexone‐ Buproprion	α‐MSH/ß‐endorphin	Possible modulation of melanocortin system	LT	Adverse GI effects; dizziness/insomnia	Approved	118
Lorcaserin	Serotonin/5HT receptor	Modulates melanocortin system	LT	Headache, weakness, bradycardia, cognitive impairment	Approved	119, 120
Leptin	POMC/NPY neurons	Modulates the melanocortin system	LT	Exogenous administration largely ineffective	Approved as combinatorial therapy	121, 122
Section III
Amphetamine compounds	POMC/NPY neurons	High metabolic rate; stimulation of anorectic/inhibition of orectic signals	Short‐term	Addictive in nature	Approved (less addictive analogues now available)	122, 123, 124
Methamphetamine desoxyephedrine	‐do‐	‐do‐	‐do‐	‐do‐	Approved	123, 125
Deoxyphedrine	‐do‐	‐do‐	‐do‐	‐do‐	Approved	126
Amphetamine congeners (AC)	‐do‐	‐do‐	‐do‐	Additive in general	Approved	127
Diethylpropion (AC)	‐do‐	‐do‐	‐do‐	Limited drug efficiency	Approved	128
Phendimetrazine (AC)	‐do‐	‐do‐	‐do‐	Insomnia, dry mouth, constipation	Approved	129
Benzphetamine (AC)	‐do‐	‐do‐	‐do‐	Insomnia, dry mouth, mood swings	Approved	130
Phentermine	‐do‐	Increased energy consumption and anorexia	‐do‐	Insomnia, dry mouth, mood swings	Approved	131, 132
Phentermine/topiramate (Qsymia)	Glutamate and GABA receptors	Weight loss and decrease in CNS neuronal activity via Ca2+ channels	‐do‐	Insomnia, dry mouth, dizziness	Approved	108, 120, 133
Section IV
MEDI0382	GLP‐1R/GCGR	Bi‐agonist targeting	—	—	Phase II	134
NNC0090‐2746 (RG7697)	GLP‐1R/GIPR	Bi‐agonist targeting	—	—	Phase IIa	135
LY3298176	GLP‐1R/GIPR	Bi‐agonist targeting	—	—	Phase II complete	136
HM15211	GLP‐1R/GCGR/GIPR	Tri‐agonist targeting	—	—	Preclinical	137
NN9423/NNC9204‐1706	GLP‐1R/GCGR/GIPR	Tri‐agonist targeting	—	—	Phase I	138
Section V
GLP‐1 delivering Estrogen	Peptide mediated hormone delivery	Peripheral/central regulation by modulation of energy sensors	Long‐term	Risk of breast cancer, heart ailments, stroke, dementia	Preclinical	139
17ß‐estradiol (E2)	‐do‐	‐do‐	Long‐term	‐do‐	Preclinical	140
Glucagon/T3	‐do‐	Modulation of energy expenditure via BAT thermogenesis	—	—	Preclinical	141
GLP‐1 delivering dexamethasone	‐do‐	Energy balance and weight loss via hypothalamic neurocircuits	—	—	Preclinical	142
Section VI
Dinitrophenol	Mitochondrial uncoupling	High metabolic rate	—	Hyperthermia, tachycardia, nausea, vomiting	Withdrawn	143
Serotonergics	Seratonin/5HT	Seratonergic/Melanocortinergic system	—	Pulmonary hypertension; valvular heart disease	Withdrawn	128, 131
Fenfluramine	‐do‐	‐do‐	—	‐do‐	Withdrawn	144, 145
Dexfenfluramine	‐do‐	‐do‐	—	‐do‐	Withdrawn	144, 145
Sibutramine	Serotonin/norepinephrine inhibitor	‐do‐	—	High BP, cardiac arrhythmia	Withdrawn	146
Rimonabant	Type I CB1R	Weight loss by modulating hemostatic and hedonic feeding circuits	—	Adverse psychiatric effects	Withdrawn	147

Section I: Antiobesity drugs targeting MC4R; Section II: General antiobesity drugs; Section III: Drugs approved for short‐term use only because of potential side effects and addictive nature. Section IV: Bi‐ and tri‐agonist drug targets (in developmental stage); Section V: Peptide‐hormone based drugs (in developmental stage); Section VI: Drugs that have been withdrawn as a result of extreme side effects.

Note: *‐do‐ Refers to repeat the exact words/content of the row above, in that specified column, to avoid writing the same information multiple times in the table.

Abbreviations: 4‐PBA, sodium 4‐phenylbutyrate; AC, adenylyl cyclase; ACTH, adrenocorticotropic hormone; BP, blood pressure; DCPMP, N‐((2R)‐3(2,4‐dichlorophenyl)‐1‐(4‐(2‐([1‐methoxypropan2‐ylamino] methyl) phenyl) piperazin‐1‐yl)‐1‐oxopropan2‐yl) propionamide; ECL, extracellular loop; GABA, gamma‐aminobutyric acid; GCGR, glucagon receptor; GI, gastrointestinal; GIPR, glucose‐dependent insulinotropic polypeptide; GLP‐1R, glucagon‐like peptide‐1 receptor; MC4R, melanocortin 4‐receptor; NBP, 1‐(1‐(4‐fluorophenyl)‐ 2‐(4‐(4‐[naphthalene‐1‐yl] butyl) piperazin‐1‐yl) ethyl)‐4‐ methylpiperazine; NPY, neuropeptide Y; POMC, proopiomelanocortin; THIQ, N‐[(3R)‐1,2,3,4‐Tetrahydroisoquinolinium‐3‐ylcarbonyl]‐(1R)‐1‐(4‐chlorobenzyl)‐2‐[4‐cyclohexyl‐4‐(1H‐1,2,4‐triazol‐1‐ylmethyl) piperidin‐1‐yl]‐2‐oxoethylamine; UBE‐41, ubiquitin activating enzyme inhibitor.