doi number J. Braz. Chem. Soc., Vol. 00, No. 00, 1-1, 2016. Printed in Brazil - ©2016 Sociedade Brasileira de Química Review 0103 - 5053 $6.00+0.00 Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides David J. Newman Newman Consulting LLC, 664 Crestwood Road, 19087 Wayne-PA, USA This relatively short review demonstrates the very important role of the structures of the natural products adrenaline and relatives, in the design and subsequent approval of β-agonists and antagonists, and of modified nucleosides as anticancer, and in particular, antiviral agents against herpes (HSV), human immunodeficiency virus (HIV) and hepatitis C virus (HCV) that would not have been synthesized in the absence of knowledge of bioactive arabinose nucleosides. Keywords: β-agonist, β-antagonist, nucleoside, natural product-based drug 1. Introduction in earlier days. This review is not meant to be exhaustive but will cover agents in use and some in late clinical trials Although adrenalin(e) (epinephrine; 1) was first isolated status, where it will be shown where the original “ideas” from adrenal glands and reported in 1901 by Takamine,1 came from in the chemical sense. a full report of his work was published a century later in 2003 by Yamashima.2 This compound can be considered 2. The Biology of Adrenergic Agents to have led to the concept of beta-adrenergic agents and their receptor subtypes,3-5 leading ultimately to the very Although not known at the time(s) of isolation and significant number of agents used in hypertension and identification of the individual agents from animal tissues allergy and in particular, the beta-blocker, propranolol (2),6 (including human), the biosyntheses of the agents easily which was a lineal chemical descendent of the earlier demonstrates why drugs designed to resemble one or more compound nethalide (3).7 of their biological effectors, often exhibit “side-effects” on Similarly, though later in time, nucleosides have been other parts of these systems. known as components of DNA (deoxyribonucleic acid) Scheme 1 shows the biosynthetic pathway for and RNA (ribonucleic acid) for a very significant number the production of the adrenergic agents from the of years, dating from at least 1932 for the structure amino acid tyrosine. As can be seen, the process goes of adenosine8 with a fuller review of the purines and through L-DOPA, then dopamine, norepinephrine pyrimidines showing the state of the art at that time was (4; noradrenaline) to epinephrine (1; adrenaline), and published by Chromtzka in 1937.9 Their history as “leads it also shows the first non-specificβ -agonist to go into to drugs” is more recent and aside from a very few agents clinical use, isoproterenol (5). The involvement of the where the base was modified chemically, no agents were dopaminergic agents in this pathway gives an indication synthesized until the reports from the Bergmann et al.10-12 as to why the agents used to activate (agonists) and block at Yale in the early to middle 1950s of arabinose-substituted (antagonists) frequently exhibit “spillover” into related nucleosides with biological activities. pathways. Thus the earlier and from the aspect of today, In this short review, it will be shown how these early simplistic pharmacology statements made in the 1940s to discoveries have led to very significant drugs against probably the late 1970s or so on specificity of adrenergic cardiovascular disease and immediate allergy and other drugs, need to be reevaluated today on the basis of current pulmonary diseases in the case of the adrenergic amine knowledge of the molecular pharmacology of receptors derivatives, and against viral diseases and cancer in the case that these agents interact with. However, that being said, of the nucleosides. None of which would have occurred if the effects of these agents and their continued usage by the basic biology and chemistry had not been elucidated physicians demonstrates that they still work. The intention of this work is to discuss agents that *e-mail: [email protected] fall into the categories of β-agonists and β-antagonists 2 Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides J. Braz. Chem. Soc. OH HO HO HO NH2 HO NH 2 NH NH 2 O 2 O HO HO OH HO H H OH Dopamine 4: Norepinephrine L-Tyrosine L-DOPA (noradrenaline) OH Chemical H OH N H modification HO HO N HO HO 1: Epinephrine (adrenaline) 5: dl-Isoproterenol Scheme 1. Biosynthesis of the adrenergic agents. and will not cover other potential adrenergic interactions. Subsequently a significant number of “selective” β-agonists The concept of β-agonists and antagonists arose from have entered the various pharmacopoeias used world-wide work performed as mentioned earlier by groups in the and they cover the three currently recognized β-agonist United Kingdom (UK) and the United States (US), with subtypes, though currently only one, as mentioned later, 3 the initial report by Ahlquist in 1948. As shown below in has been approved for the β3-agonist subtype. Table 1, there are currently three classes of β-receptors Early and some later examples are shown in Figures 1 recognized by their responses to the two natural compounds (for β1,2-agonists) and 2 (for β3-agonists) where the date of epinephrine “E” (1) and norepinephrine “NE” (4), and the approval by the US FDA (Food and Drug Administration) or isopropyl analogue of “NE”, the first synthesizedβ -agonist its equivalent are shown in Table 2 (for all three types), with isoproterenol “Iso” (5) which was first used in Germany a note as to their “selectivity” against the various receptor in 1940,13-15 and which is still in use as a treatment for subtypes (where known). Table 2 and the accompanying asthma. Further information on the β3-receptor is given structures are not meant to be complete, they are simply later in the review. examples drawn mainly from listings of such drugs in the reviews by Newman and Cragg.16-18 3. Drugs Based on Epinephrine and Norepi- Inspection of the compounds in Figure 1 demonstrates nephrine how medicinal chemists built upon the basic structure of adrenaline (1) and noradrenaline (4) to first derive 3.1. β-Agonists isoproterenol (5) a simple variation in the amino substituent (isopropyl for methyl in this case), but it still had non- In the early days of work in this area, as mentioned specific β-agonist activity being effectively equipotent above, isoproterenol (5) was the gold standard for against the β1 and β2 receptors as defined initially by 3 β-agonists and even though it is now close to 80 years Ahlquist in 1948, and there is now a third, or β3 receptor since its initial synthesis (see references in Konzett’s 1981 identified. The later methodologies involved the use of article)15 and though it is now over 75 years since its initial radioligand displacement linked to activation of adenylate use in 1940, it is still in the physician’s armamentarium, cyclase, and some of the early work on this technique, though it is not selective in terms of the β-receptor subtypes. which is still in use, can be seen by inspection of the paper Table 1. Pharmacological definition ofβ -receptors Receptor Agonist Tissue Pharmacological response β1 Iso > E = NE juxtaglomerular cells heart increased renin secretion increased force and rate of contraction β2 Iso > E >> NE smooth muscle (vascular and bronchial, relaxation gastrointestinal and genito-urinary) β3 Iso = NE > E adipose tissue lipolysis E: epinephrine; NE: norepinephrine; Iso: isoproterenol. Vol. 00, No. 00, 2016 Newman 3 OH OH OH H OH H HO N H HO N HO NH 2 HO N HO HO HO HO 1: Adrenaline (epinephrine) 4:Noradrenaline (norepinephrine) 5: Isoproterenol (isoprenaline) 6:Dobutamine, 1978 Non-specific β-agonist Non-specific β-agonist Non-specific β-agonist β1-Agonist OH O HO HN OH H OH O N H O N N N H O HO HO HO 9: Xamoterol, 1988 7:Butopamine (1980+) 8: Prenalterol, UK, 1980s β1-Agonist Alzheimer’s (preclinical 2015) β1-Agonist β1-Agonist OH OH OH H OH H H HO N H N HO N N HO S OO HO HO OH OH 12:Metaproterenol (alupent) 13:Sulfonterol (1980?) 10:Salbutamol, 1968 11:Terbutaline; 1970 β -Agonist β2-Agonist β2-Agonist 2 β2-Agonist (active clinical trials 2015) Launched France 1971 (withdrawn 2010) OH OH H N OH H HO O H H Cl N N N OH O HO O H2N OH HO O Cl 14:Eformoterol; 1986 15:Clenbuterol, 1986 β2-Agonist (also COPD) 16:Salmeterol xinafoate; 1990 β2-Agonist (Pompe's β2-Agonist disease, PH I/II; 2015) OH H O N O OH HO H HN N HO O OH 17:Levosalbutamol, 2000+ β2-Agonist 18:Olodaterol 2013/4 (Lupus PH II 2015) β2-Agonist OH OH H H N O N O Cl HO H NH O N N H HO O N OH O 19:Batefenterol (PH II, 2015) 20:Higenamine (norcoclaurine) β2-Agonist (also muscarinic β2-Agonist (PH I, 2015I) receptor antagonist) Nandina domestica (leaves) Figure 1. Non-specificβ and β1- and β2- specific agonists. 4 Natural Product-Derived Drugs Based on β-Adrenergic Agents and Nucleosides J. Braz. Chem. Soc. Table 2. Approved and clinical Phase I-III β-receptor agonists Name Number Specificity Date approved (if known & comments) Dobutamine 6 β1-selective 1978 Butopamine 7 β1-selective 1980+ (not USA) Prenalterol 8 β1-selective 1980s (UK) Xamoterol 9 β1-selective 1988 (now preclinical in Alzheimer’s) Salbutamol 10 β2-selective 1968 (still active clinical trials) Terbutaline 11 β2-selective 1970 (UK) Metaproterenol 12 β2-selective 1971 (France; withdrawn 2010) Sulfonterol 13 β2-selective 1980? (UK) Eformoterol 14 β2-selective 1986 (Japan; now COPD) Clenbuterol 15 β2-selective 1986 (EU/Japan; now Phase I/II Pompe’s disease) Salmeterol 16 β2-selective 1990 Levosalbutamol 17 β2-selective early 2000s (now Phase II for lupus) Olodaterol 18 β2-selective 2013/4 Batefenterol 19 β2-selective Phase II (also Muscarinic receptors; COPD) Higenamine (norcoclaurine) 20 β2-selective natural product Phase I Mirabegron 21 β3-selective 2012 (Japan, US, EU) Solabegron 22 β3-selective Phase II/III Ritobegron 23 β3-selective Phase I ? COPD: chronic obstructive pulmonary disease; USA: United States of America; UK: United Kingdom; EU: European Union.