The β₃ (beta 3) adrenergic receptor agonist or β₃-adrenoceptor agonist, also known as β₃-AR agonist, are a class of medicine that bind selectively to β₃-adrenergic receptors. β₃-AR

agonist An agonist is a chemical that activates a Receptor (biochemistry), receptor to produce a biological response. Receptors are Cell (biology), cellular proteins whose activation causes the cell to modify what it is currently doing. In contrast, an R ...

s for the treatment of

obesity Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...

and

type 2 diabetes Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...

have been in developmental stages within many large pharmaceutical companies since the early 1990s without successfully delivering an anti-obesity product to the market. More recently pharmaceutical companies have developed selective β₃-AR agonists targeted at urinary inconsistencies and in 2012

Mirabegron Mirabegron, sold under the brand name Myrbetriq among others, is a medication used to treat overactive bladder. Its benefits are similar to antimuscarinic medication such as solifenacin or tolterodine. It is taken by mouth. Common side effect ...

(trade name Myrbetriq and Betmiga) was the first β₃-AR agonist to be approved in the United States and Europe for the treatment of overactive bladder (OAB) syndrome.

Medical Uses

In 2018 only one β₃-AR agonist is approved by the

European Medicines Agency The European Medicines Agency (EMA) is an agency of the European Union (EU) in charge of the evaluation and supervision of pharmaceutical products. Prior to 2004, it was known as the European Agency for the Evaluation of Medicinal Products ...

(EMA) and the

Food and drug Administration The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respo ...

(FDA) as a medicine. The medicine is called Mirabegron and is used to treat OAB.

Urinary bladder

is a selective β₃-AR agonist that affects the

detrusor muscle The detrusor muscle, also detrusor urinae muscle, muscularis propria of the urinary bladder and (less precise) muscularis propria, is smooth muscle found in the wall of the bladder. The detrusor muscle remains relaxed to allow the bladder to s ...

s of the

urinary bladder The bladder () is a hollow organ in humans and other vertebrates that stores urine from the Kidney (vertebrates), kidneys. In placental mammals, urine enters the bladder via the ureters and exits via the urethra during urination. In humans, the ...

. By stimulation of β₃-AR the contraction of the

smooth muscle Smooth muscle is one of the three major types of vertebrate muscle tissue, the others being skeletal and cardiac muscle. It can also be found in invertebrates and is controlled by the autonomic nervous system. It is non- striated, so-called bec ...

s of the bladder is decreased and the bladder can store more volume of urine at a given time. Mirabegron also has an influence on the non-

voiding Urination is the release of urine from the bladder through the urethra in placental mammals, or through the cloaca in other vertebrates. It is the urinary system's form of excretion. It is also known medically as micturition, voiding, ures ...

contraction by decreasing the frequency of the contractions. Vibegron

In 2018 two other β₃-AR agonists are in

clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...

vibegron Vibegron, sold under the brand name Gemtesa, is a medication for the treatment of overactive bladder. Vibegron is a selective beta-3 adrenergic receptor agonist. The most common side effects include headache, urinary tract infection, common ...

and solabegron. Vibegron is in phase 3 clinical trial and is used to treat OAB. Solabegron is in phase 2b clinical trials to treat OAB in women and in phase 1 clinical trials in men to treat OAB.

Obesity and diabetes

The β₃-AR has been linked to

thermogenesis Thermogenesis is the process of heat production in organisms. It occurs in all warm-blooded animals, and also in a few species of thermogenic plants such as the Eastern skunk cabbage, the Voodoo lily ('' Sauromatum venosum''), and the giant w ...

in human

skeletal muscle Skeletal muscle (commonly referred to as muscle) is one of the three types of vertebrate muscle tissue, the others being cardiac muscle and smooth muscle. They are part of the somatic nervous system, voluntary muscular system and typically are a ...

s, with studies showing it to be responsible for over 40% of

ephedrine Ephedrine is a central nervous system (CNS) stimulant and sympathomimetic agent that is often used to prevent hypotension, low blood pressure during anesthesia. It has also been used for asthma, narcolepsy, and obesity but is not the preferred ...

-induced thermogenesis.

Cardiovascular

In March 2016 a study funded by the

European Commission The European Commission (EC) is the primary Executive (government), executive arm of the European Union (EU). It operates as a cabinet government, with a number of European Commissioner, members of the Commission (directorial system, informall ...

began. The study is assessing the efficacy of Mirabegron in prevention of

heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to Cardiac cycle, fill with and pump blood. Although symptoms vary based on which side of the heart is affected, HF ...

. In 2018 the study is ongoing and it's expected to conclude in 2020. A selective β₁-AR antagonist with additional β₃-AR agonist activity, called

nebivolol Nebivolol is a beta blocker used to treat high blood pressure and heart failure. As with other β-blockers, it is generally a less preferred treatment for high blood pressure. It may be used by itself or with other blood pressure medication. ...

, is one of a few selective B₁-AR antagonists known to also cause vasodilation. This peripheral vasodilation is mediated by endothelial nitric oxide release following β₃-AR agonism, not by adrenergic receptor blockade. This means nebivolol exerts vasodilatory, cardioprotective effects without the added adrenergic block side effects seen with non-selective beta-blockers that concomitantly lower blood pressure. Nebivolol is therefore approved for hypertension therapy in the United States; however, beta-blockers are still not generally the first line of treatment for primary hypertension.ool

Mechanism of action

β₃-AR are coupled with

G proteins G proteins, also known as guanine nucleotide-binding proteins, are a family of proteins that act as molecular switches inside cells, and are involved in transmitting signals from a variety of stimuli outside a cell to its interior. Their ...

, both G_s protein and G_i protein. G_s protein coupled with β₃-AR lead to increased activity of the

enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...

adenylyl cyclase Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction: :A ...

. Increased activity of adenylyl cyclase leads to increased formation of

cyclic adenosine monophosphate Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger, or cellular signal occurring within cells, that is important in many biological processes. cAMP is a derivative of adenosine tri ...

(cAMP). β₃-AR can also couple with G_i proteins. When they are coupled they lead to decrease in

intracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

cAMP. The mechanism of β₃-AR and G_i protein has been proposed as a mechanism of action in the heart. When β₃-AR are coupled with G_i protein they can act as a brake on β₁- and β₂ adrenergic receptors to prevent over-activation by opposing the classical

inotropic An inotrope or inotropic is a drug or any substance that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular co ...

effect of β₁ and β₂ adrenergic receptors. The smooth muscle cells in the urinary bladder express β₃-AR. They have effect on the detrusor muscle which relaxes when the β₃-AR are activated. The relaxed detrusor muscle improves filling capacity of the bladder and eases the urge to pass urine.

Nitric oxide

Another mechanism by which β₃-AR agonists exert their relaxative effects on vasculature is by promoting endothelial nitric oxide synthase (eNOS) activity and NO bioavailability. This is believed to be the mechanism by which

, a selective β₁-AR antagonist with additional β₃-AR agonist activity, exerts its cardio-protective effects.

Structure Activity Relationships (SAR)

Basic structure of β₃-adrenergic receptor agonists

β₃-AR agonists have the basic structure 2-amino-1-phenylethan-1-ol but have variations that affect the selectivity of the agonist.

Binding to the β₃-adrenergic receptor

Visual inspection of selective β₃-AR agonists revealed that they bind deep in the binding pocket of the receptors and exhibit some H-bonds and or hydrophobic interactions with the receptor.

Activity of β₃-adrenergic receptor agonists

Basic_structure_for_beta_3_adrenergic_receptor_agonist

The R-group on the following picture determines α- or β-adrenergic receptor selectivity. The larger the R-group is, the greater the β-receptor selectivity. The basic structure of β-AR subtypes exhibit sequence similarity greater than 70% suggesting that the 3-dimensional structure of theses subtypes is similar. While the overall structure sequence is 70% identical the residue sites of the

ligand In coordination chemistry, a ligand is an ion or molecule with a functional group that binds to a central metal atom to form a coordination complex. The bonding with the metal generally involves formal donation of one or more of the ligand's el ...

binding pocket have an even higher similarity (75%-85%), making development of highly selective ligands difficult. The β₃-AR unlike other β-adrenergic receptors has a higher affinity to ligands with a pyrimidine or ''m''-chlorobenzyl ring rather than catecholamine like the other beta receptors subtypes. Noticeable ligand binding sites are the hydrophobic interaction of the aromatic ring, attached to the β-hydroxyl chiral carbon on the left-hand-side, to hydrophobic microdomains on TM3 and TM6 deep in the binding pocket. Additional hydrophobic side groups attached on this aromatic ring have been shown to increase hydrophobic contact in this region. The central hydroxyl group and the central protonated amine form strong hydrogen bonds with the TM7 and TM3 subunits. The hydrogen bonding of the central protonated amine to Y³³⁶ on the TM7 of the β₃-AR serves as an important binding site for the ligand, aligning it properly for the deeper hydrophobic interaction between LHS aromatic ring and TM3 and TM6. This interaction is consistent between the ligands. Most of the selective agonists have an aromatic ring formation or another hydrophobic region, around 2-3 carbons from the central protonated amine group, which interacts with the superficial

extracellular This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...

(ELC2) domain on the receptor. The

stereochemistry Stereochemistry, a subdiscipline of chemistry, studies the spatial arrangement of atoms that form the structure of molecules and their manipulation. The study of stereochemistry focuses on the relationships between stereoisomers, which are defined ...

of this aromatic group and its interactions with the ECL2 affect the ability of the ligand to align properly in the deep binding pocket and is an important factor for the total affinity of the ligand. The addition of a proton donating group (e.g. acid, amide) on the right-hand-side terminus contributes to a strong bifurcated hydrogen bonding to the R³¹⁵ of TM6. Those ligands that do not have an acidic group have some other form of strong hydrogen bonding group that interacts with R³¹⁵, such as a thiazole. This binding site differs between the different beta receptors subtypes and contributes to the β₃ selectivity.

History of development

In 1984 the β₃ receptor was described as the third group of beta receptors in adipose tissue. This led to the development of agonist targeted at obesity and diabetes. In 1999 the function of the β₃ in

s was defined which opened the way for development of β₃-AR agonist for OAB. In 2001

began clinical development in phase 1 clinical study. The indications were type 2 diabetes,

lower urinary tract symptoms Lower urinary tract symptoms (LUTS) refer to a group of clinical symptoms involving the bladder, urinary sphincter, urethra and, in men, the prostate. The term is more commonly applied to menover 40% of older men are affectedbut lower urinary t ...

, OAB and bladder outlet obstruction. From 2004 to 2008 phase 2 clinical trials were performed. However the development of

for type two diabetes was interrupted. In 2007

GlaxoSmithKline GSK plc (an acronym from its former name GlaxoSmithKline plc) is a British Multinational corporation, multinational Pharmaceutics, pharmaceutical and biotechnology company with headquarters in London. It was established in 2000 by a Mergers an ...

entered phase 1 clinical trials with Solabegron with the indication for OAB as well as a trial with the indication for Irritable bowel syndrome (IBS).{{Cite news, url=https://clinicaltrials.gov/ct2/show/NCT00401479?term=solabegron&rank=6, title=A Study To Investigate The Effect Of Solabegron (GW427353) On Gastrointestinal Transit In Healthy Volunteers - Full Text View - ClinicalTrials.gov, access-date=2018-10-03 From 2009 to 2011

Astellas Pharma is a Japanese multinational pharmaceutical company, formed on 1 April 2005 from the merger of and . Astellas is a member of the Mitsubishi UFJ Financial Group (MUFJ) keiretsu. History Early foundations Fujisawa Shoten was started in 1894 ...

concluded phase 3 clinical trials for the treatment of OAB with

mirabegron Mirabegron, sold under the brand name Myrbetriq among others, is a medication used to treat overactive bladder. Its benefits are similar to antimuscarinic medication such as solifenacin or tolterodine. It is taken by mouth. Common side effect ...

. In July 2012 mirabegron was the first β₃-AR agonist to be approved by the FDA and in October the same year it was approved by EMA. In 2011 Merck & Co. entered clinical trials with vibegron with the indication for OAB. and phase III clinical trials began in 2018. In 2018 solabegron, which has been acquired by Velicept Therapeutics, Inc., started phase I and phase II clinical trials in men and women, respectively, for the indication of OAB.

Medical Uses

Urinary bladder

Obesity and diabetes

Cardiovascular

Mechanism of action

Nitric oxide

Structure Activity Relationships (SAR)

Basic structure of β₃-adrenergic receptor agonists

Binding to the β₃-adrenergic receptor

Activity of β₃-adrenergic receptor agonists

History of development

See also

References

Medical Uses

Urinary bladder

Obesity and diabetes

Cardiovascular

Mechanism of action

Nitric oxide

Structure Activity Relationships (SAR)

Basic structure of β3-adrenergic receptor agonists

Binding to the β3-adrenergic receptor

Activity of β3-adrenergic receptor agonists

History of development

See also

References

Basic structure of β₃-adrenergic receptor agonists

Binding to the β₃-adrenergic receptor

Activity of β₃-adrenergic receptor agonists