β3 Pharmaceuticals
Justin Cropsey
CHEM 4201
Dr. Sheppard
20 November 2014
Overview
 Receptor Overview
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Adrenoceptors
G-Proteins
β3 Receptor
β3 Differences
 Pharmacology Hurdles
 β3 Hurdles
 Structures
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Endogenous Ligands
Non-selective Endogenous Ligands with Partial Activity
Endogenous Ligands with Inefficient β-AR Activity
β1 Blockers
SABAs, LABAs, and β2 Blockers
β3 Agonists Under Development
Adrenoceptors
 Family includes:
 β1 predominant in the heart
 β2 predominant in the lungs
 β3 found throughout
 β4??
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Some evidence suggests may exist.
 Various α receptors
 Endogenous ligands (Catecholamines)
 Epinephrine (Adrenaline)
 Norepinephrine (Noradrenaline)
 All are G-proteins
G-proteins
 Integral membrane proteins
 Transduce extracellular signal to interior
 Consist of 3 subunits—α, β, γ
 Convert GTP to GDP
 Molecular Clock
 Gα (Adenylyl Cyclase)
 ATP  cAMP
 Intracellular Second-Messenger Signal
 Can be inhibitory or stimulatory
β3 Receptor
 7-pass Transmembrane Protein
 Found throughout body
 Higher concentrations exist in:
 Neural Tissues (Anxiety)
 Cardiac Tissues (Contractile Force)
 Endothelium (Vasodilation)
 White Adipose Tissue (Lipolysis)
 Brown Adipose Tissue (Thermogenesis)
 Intestines (Smooth-Muscle Relaxation)
 Urinary Bladder (Smooth-Muscle Relaxation)
β3 Structure
β3 Differences
 Gene contains introns
 Protein is not phosphorylated by Protein Kinase A nor β
Adreno-Receptor Kinase
 Resistance to Desensitization
 Also has NO synthase as an effector
 Upregulation in Disease
 Diverse tissue distribution
 Octopamine
Pharmacological Hurdles
 Administration
 Oral delivery, if possible (Must be acid-stable!)
 Pharmacokinetics
 Liberation – Freeing the drug from the formulation
 Time-released
 Absorption – Getting the drug into the body
 Bioavailability – How much was actually absorbed
 Distribution – Where does the drug go in the body
 Fat-solubility
 Sequestration by blood serum
 Metabolism – Where is the drug broken down and to what
 Liver, Kidneys
 Excretion – How does the body rid itself of the drug
β3 Hurdles
 Translation from rodents to humans
 E.g., Lipolysis in humans is less dependent on β3 receptor.
 Ubiquity of β3 receptor
 Lots of potential for side effects
 E.g., Bladder medication increasing Free-Fatty Acids in the
blood and causing overheating!
 β1 and β2 co-activation or inhibition
 Heart rate, blood pressure, dyspnea
 Toxicity
Endogenous Ligands
Ligand
β3
Structure
Epinephrine
Norepinephrine
Octopamine
No
No
Yes
Ligands w/ Inefficient β-AR Activity
Dopamine
Tyramine
 Notice the lack of the β-hydroxyl group.
β-phenylethylamine
Ligands w/ Partial β-AR Activity
Synephrine
Phenylethanolamine
Epinine
β Blockers (Antagonists)
Pharmaceutical
Acebutolol
Pindolol
Nadolol
β1 Selective
Yes
No
No
Intrinsic
Sympathomimetic
Activity
Yes
Yes
No
SABAs, LABAs, and β2 Blockers
Pharmaceutical
Type
Albuterol
Formoterol
Butaxamine
SABA
LABA
β2 Blocker
Oxadiazolidinedione β3 Agonists
 Developed by Wyeth-Ayerst
 259-fold selectivity over β1
 754-fold selectivity over β2
Benzimidazolone β3 Agonists
 Developed by Eli Lilly & Company
 Modulates atrial tachycardia thru steric bulk at the 3-position of the
benzimidazolone moiety
 R1 = {H, Me, Et, tBu, CH2-cyclopropyl,CH2-cyclobutyl, CH2-cyclopentyl}
 Little to no agonist activity at the β1 nor β2 receptors
Oxindole β3 Agonists
 Developed by Eli Lilly & Company
 Modulates atrial tachycardia thru substitution at the 3-position of the
oxindole moiety
 R1 = {H, Me, Et, iBu, Bn}
 R2 = {H, Me, Et, Bn}
Written Assignment
 Poster describing the potential pharmaceuticals and the
various hurdles being encountered.
References
 Arch, J. R. (2011). Challenges in β3-adrenoceptor agonist drug development.
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Therapeutic advances in endocrinology and metabolism, 2042018811398517.
Brunton L L, Blumenthal D K, Murri N, Dandan R H, Knollmann B C. Goodman
& Gilman's The Pharmacological Basis of Therapeutics. 11th ed. New York: McGrawHill, 2005.
Carpéné, C., Galitzky, J., Fontana, E., Atgié, C., Lafontan, M., & Berlan, M.
(1999). Selective activation of β3-adrenoceptors by octopamine: comparative
studies in mammalian fat cells. Naunyn-Schmiedeberg's archives of pharmacology,
359(4), 310-321.
Finley, D. R., Bell, M. G., Borel, A. G., Bloomquist, W. E., Cohen, M. L.,
Heiman, M. L., ... & Jesudason, C. D. (2006). Potent benzimidazolone based
human β3-adrenergic receptor agonists. Bioorganic & medicinal chemistry letters,
16(21), 5691-5694.
Hu, B., Malamas, M., Ellingboe, J., Largis, E., Han, S., Mulvey, R., & Tillett, J.
(2001). New oxadiazolidinedione derivatives as potent and selective human β3
agonists. Bioorganic & medicinal chemistry letters, 11(8), 981-984.
References (cont’d)
 Preitner, F., Muzzin, P., Revelli, J. P., Seydoux, J., Galitzky, J., Berlan, M., ... &
Giacobino, J. P. (1998). Metabolic response to various β-adrenoceptor agonists
in β3-adrenoceptor knockout mice: Evidence for a new β-adrenergic receptor
in brown adipose tissue. British journal of pharmacology, 124(8), 1684-1688.
 Skeberdis, V. A. (2003). Structure and function of beta3-adrenergic receptors.
Medicina (Kaunas, Lithuania), 40(5), 407-413.
 Stevens, F. C., Bloomquist, W. E., Borel, A. G., Cohen, M. L., Droste, C. A.,
Heiman, M. L., ... & Jesudason, C. D. (2007). Potent oxindole based human β3
adrenergic receptor agonists. Bioorganic & medicinal chemistry letters, 17(22),
6270-6273.
 Yamaguchi, O., & Chapple, C. R. (2007). β3-Adrenoceptors in urinary bladder.
Neurourology and urodynamics, 26(6), 752-756
Questions?