Annual Activities Report 2011 - INCT-Inofar - UFRJ

Annual Report 2011 | INCT-INOFAR
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Highlights
Many of the non-polar aliphatic amino acids, such as glycine, alanine, valine, isoleucine, leucine and
methionine, differ solely through homologation or inversion of the positions of methyl groups (Figure 1B).
For example, isoleucine has one homologated methyl in comparison to valine. Moreover, alanine is the
methyl-homologue of glycine.
Morphine was first described in 1805 by the German pharmacist Sertürner, 5,6 although it was originally
isolated by Seguin and Courtois in 1804. 7 Sertürner described the isolation of a white alkaline solid with
hypnotic properties, which he called morphine after the Greek god of sleep Morpheus. 5,6 The complex
chemical structure of morphine was fully elucidated by Sir Robert Robinson in 1925, 8 who was awarded
a Nobel Prize in Chemistry in 1947. Morphine provides a good illustration of the importance of methyl
groups and how their simple introduction or removal may significantly alter the pharmacological activity of a
bioactive compound, leading to different pharmacokinetic and pharmacodynamic profiles.
Studies of the structure-activity relationships of morphine revealed that removal of the methyl group attached
to the sp 3 nitrogen of its benzylisoquinoline ring to generate normorphine causes ca. 6-fold reduction in in
vivo analgesic activity (morphine ED 50
= 4.8 mg/kg and normorphine ED 50
= 31.5 mg/kg in mice). 9 On the
other hand, the simple O-methylation of morphine’s phenolic hydroxyl group at C-3 generate codeine (Figure
1C) 10 reduces its receptor affinity by 200-fold, 11 demonstrating that methyl groups may also have a negative
influence on activity. In this case, the presence of an additional methyl group of codeine reduces its interaction
with opioid receptors because the phenolic hydroxyl group of morphine is responsible for the hydrogen bond
interactions with the target receptor site (Figure 1C). 12,13 Despite being 200-fold less potent in vitro, codeine is
only 3-fold less potent than morphine in vivo (codeine ED 50
= 14.5 mg/kg in mice), 9 enabling this drug could
be used for the treatment of moderate pain, cough, and diarrhea. 14
The importance of naturally methylated products as prototype substances for the development of new drugs
can be observed in the history of the discovery of compactin. 15 This hexahydronaphthalene derivative is the
source for antilipemic agents known as statins; in fact, the statin atorvastatin (Lipitor®) is currently the bestselling
drug worldwide (Figure 1D). 16 All of the statins structures contain two methyl groups in an isopropyl
group connected to the central heterocyclic system. These methyl groups are important for activity due to their
involvement in hydrophobic interactions with Leu562, Cys561 and His752, which create an entropic gain
in the interaction with the target receptor. The removal of the methyl groups leads to an 18-fold reduction in
potency, as shown in initial structure-activity relationship studies with certain pyrrole derivatives. 17
Omeprazole (Losec®), is a pyrimidinyl-benzoimidazol derivative with important antiulcer properties, was the
first selective gastric H + -K + -ATPase inhibitor, which are also referred to as proton pump inhibitors (PPIs)
(Figure 1E). 18 Structure-activity relationship studies of omeprazole showed that the introduction of methyl
groups into the pyridine ring, due to their electron-donating effects, is beneficial for activity and increases its
potency against H + -K + -ATPase. The introduction of methyl groups into these inhibitors allows fine tuning