Current Topics in Medicinal Chemistry, Volume 4, No. 4, 2004
Contents
Modern Aspects in the Design And Discovery
of Novel Antihypertensive Drugs
Guest Editor: Thomas Mavromoustakos
Conformation
and Bioactivity. Design and Discovery of Novel Antihypertensive Drugs Pp. 385-401
T. Mavromoustakos, M. Zervou, P. Zoumpoulakis, I.
Kyrikou, N.P. Benetis, L. Polevaya, P. Roumelioti, N. Giatas, A. Zoga, P.
Moutevelis Minakakis, A. Kolocouris, D. Vlahakos, S. Golic Grdadolnik, J.
Matsoukas
Structural
Features of Angiotensin-I Converting Enzyme Catalytic Sites: Conformational
Studies in Solution, Homology Models and Comparison with Other Zinc
Metallopeptidases Pp.
403-429
Georgios A. Spyroulias, Athanassios S. Galanis, George
Pairas, Evy Manessi-Zoupa and Paul
Cordopatis
On the
Structural Basis of the Hypertensive Properties of Angiotensin II: A Solved
Mystery or a Controversial Issue? Pp. 431-444
Andreas G. Tzakos, Ioannis P. Gerothanassis and Anastassios N. Troganis
Efforts to
Understand the Molecular Basis of Hypertension Through Drug:Membrane
Interactions Pp. 445-459
T. Mavromoustakos, P. Zoumpoulakis, I. Kyrikou, A.
Zoga, E. Siapi, M. Zervou, I. Daliani, D. Dimitriou, A. Pitsas, C. Kamoutsis,
P. Laggner
Simulating
Physiology and Methods for Therapeutic Evaluation with Emphasis on Hypertension Pp. 461-471
A.K. Macpherson
and S. Neti
Renin-angiotensin
System Blockade at the Level of the Angiotensin Converting Enzyme or the
Angiotensin Type-1 Receptor: Similarities and Differences Pp. 473-481
George S. Stergiou
and
Hematocrit-lowering
Effect Following Inactivation of Renin-Angiotensin System with Angiotensin
Converting Enzyme Inhibitors and Angiotensin Receptor Blockers Pp. 483-486
K.P. Marathias, B. Agroyannis, T. Mavromoustakos, J. Matsoukas and D.V. Vlahakos
The Shift in
the “Paradigm” of the Pharmacology of Hypertension Pp. 487-498
Christodoulos S. Flordellis, Dimitrios Goumenos, George Kourounis, Sotirios A. Tsementzis, Herve Paris and Jaannis Vlachojiannis
Abstracts
[Back to top] Conformation
and Bioactivity. Design and Discovery of Novel Antihypertensive Drugs
T. Mavromoustakos, M. Zervou, P. Zoumpoulakis, I.
Kyrikou, N.P. Benetis, L. Polevaya, P. Roumelioti, N. Giatas, A. Zoga, P.
Moutevelis Minakakis, A. Kolocouris, D. Vlahakos, S. Golic Grdadolnik, J.
Matsoukas
Peptidomimitism is applied to the medicinal chemistry in order to synthesize drugs that devoid of the disadvantages of peptides. AT1 antagonists constitute a new generation of drugs for the treatment of hypertension designed and synthesized to mimic the C-terminal segment of Angiotensin II and to block its binding action on AT1 receptor. An effort was made to understand the molecular basis of hypertension by studying the conformational analysis of Ang II and its derivatives as well as the AT1 antagonists belonging to SARTANs class of molecules. Such studies offer the possibility to reveal the stereoelectronic factors responsible for bioactivity of AT1 antagonists and to design and synthesize new analogs. An example will be given which proves that drugs with better pharmacological and financial profiles may arise based on this rational design.
[Back to top] Structural
Features of Angiotensin-I Converting Enzyme Catalytic Sites: Conformational
Studies in Solution, Homology Models and Comparison with Other Zinc
Metallopeptidases
Georgios A. Spyroulias, Athanassios S. Galanis, George
Pairas, Evy Manessi-Zoupa and Paul
Cordopatis
Angiotensin-I Converting Enzyme (ACE) is a Zinc Metallopeptidase of which the three-dimensional stucture was unknown until recently, when the Xray structure of testis isoform (C-terminal domain of somatic) was determined. ACE plays an important role in the regulation of blood pressure due to its action in the frame of the Renin-Angiotensin System. Efforts for the specific inhibition of the catalytic function of this enzyme have been made on the basis of the X-ray structures of other enzymes with analogous efficacy in the hydrolytic cleavage of peptide substrate terminal fragments. Angiotensin-I Converting Enzyme bears the sequence and topology characteristics of the well-known gluzincins, a sub-family of zincins metallopeptidases and these similarities are exploited in order to reveal common structural elements among these enzymes. 3D homology models are also built using the X-ray structure of Thermolysin as template and peptide models that represent the amino acid sequence of the ACE’s two catalytic, zinc-containing sites are designed and synthesized. Conformational analysis of the zinc-free and zinc-bound peptides through high resolution 1H NMR Spectroscopy provides new insights into the solution structure of ACE catalytic centers. Structural properties of these peptides could provide valuable information towards the design and preparation of new potent ACE inhibitors.
[Back to top] On the
Structural Basis of the Hypertensive Properties of Angiotensin II: A Solved
Mystery or a Controversial Issue?
Andreas G. Tzakos, Ioannis P. Gerothanassis and Anastassios N. Troganis
Angiotensin II (AII), Asp1-Arg2-Val3-Tyr4-Ile5-His6-Pro7-Phe8, the primary active hormone of the Renin-Angiotensin-System (RAS), is a major vasoconstrictor implicated in the cause of hypertension. To unravel the question of the biologically active conformation(s) of this flexible peptide hormone and to better understand the stereoelectronic requirements that lead to the molecular basis of hypertension, we will analyze research efforts in the identification of pharmacophoric groups of AII and three general approaches for structural characterisation: the free peptide - ligand approach, the receptor based approach, and approaches that target the peptide - receptor complex. The free peptide – ligand based approach can be further categorized to: (a) conformational analysis of AII and linear peptide analogues in aqueous solution; (b) the use of solvents of medium dielectric constants; (c) conformationally restricted analogues, with emphasis to cyclic analogues; (d) the use of receptor – simulating environments, and (e) non-peptide mimetics. The receptor and peptide - receptor based approaches can be categorised to: (a) The use of monoclonal antibodies and (b) the generic description of AII receptor sites through homology modelling and mutagenesis studies. These investigations, with particular emphasis to recent developments, have greatly assisted in the identification of pharmacophoric groups for receptor activation and the development of several models of AII - receptor complexes.
[Back to top] Efforts to
Understand the Molecular Basis of Hypertension Through Drug:Membrane Interactions
T. Mavromoustakos, P. Zoumpoulakis, I. Kyrikou, A.
Zoga, E. Siapi, M. Zervou, I. Daliani, D. Dimitriou, A. Pitsas, C. Kamoutsis,
P. Laggner
Biological membranes play an essential role in the drug action. They constitute the first barrier for drugs to exert their biological action. AT1 antagonists are amphiphilic molecules and are hypothesized to act on AT1 receptor through incorporation (first step) and lateral diffusion through membrane bilayers (second step). Various biophysical methods along with Molecular Modelling were applied in order to explore the plausible two step proposed mechanism of action for this class of antihypertensive drugs.
[Back to top] Simulating
Physiology and Methods for Therapeutic Evaluation with Emphasis on Hypertension
A.K. Macpherson
and S. Neti
Improvements in therapy are aimed
at better diagnosis and more effective treatment. The use of computer
simulation has the potential to improve therapy in both ways. Computational
methods have been used extensively in diagnosis, for interpreting
MRI results, CAT scans and the development of treatments in the study of
biochemical structure. The present review examines how simulation may be used
to play a more fundamental role in therapeutic treatment often referred to as
In Silico Biology. Simulation of cells, organs and systems, such as pulmonary
and cardiovascular, can be used in clinical practice to improve diagnosis.
Initially these developments will probably have to be refined before being used
in general practice. However, when these simulations are linked with artificial
intelligence techniques containing experimental databases then very powerful
tools will result. The use of simulation in the design and development of new
drugs can both be cost and time effective. Again, artificial intelligence
techniques are likely to play an important role in evaluating patient risk
factors and unwanted side effects.
[Back to top] Renin-angiotensin
System Blockade at the Level of the Angiotensin Converting Enzyme or the
Angiotensin Type-1 Receptor: Similarities and Differences
George S. Stergiou
and
The development of drugs which block the renin-angiotensin system (RAS) has been proven a major advance in cardiovascular medicine. Angiotensin converting enzyme (ACE) inhibitors, which block the formation of angiotensin II from the inactive angiotensin I, are widely used as first line treatment in hypertension, heart failure and diabetic nephropathy. More recently, selective antagonists of the angiotensin type-1 receptor (AT1R) have become available for clinical use. Accumulating evidence suggests that AT1R antagonists have similar effects to ACE inhibitors in hypertension, heart failure and diabetic nephropathy. Although ACE inhibitors and AT1R antagonists block the same system, experimental evidence suggest that their mechanisms of action differ in several respects, such as increased bradykinin and angiotensin 1-7 levels with ACE inhibitors and AT2R activation with AT1R antagonists. Nevertheless, the clinical significance of these differences remains largely unknown and, in practice, the only clear advantage of AT1R antagonists over ACE inhibitors is the absence of cough as a side effect. Recent clinical data suggest that combined ACE inhibition and AT1R antagonism offer additive effects in reducing blood pressure in hypertension, in reducing proteinuria in nephropathy and in improving prognosis in heart failure. Further evidence suggests that some hypertensive patients may have a good antihypertensive response with ACE inhibition but not with AT1R antagonism, or the reverse. These data suggest that these two drug classes have important similarities, because they act on the same system, but they also appear to have important differences, which are not only of theoretical but also of clinical importance.
[Back to top] Hematocrit-lowering
Effect Following Inactivation of Renin-Angiotensin System with Angiotensin
Converting Enzyme Inhibitors and Angiotensin Receptor Blockers
K.P. Marathias, B. Agroyannis, T. Mavromoustakos, J. Matsoukas and D.V. Vlahakos
Several clinical and experimental observations suggest that an intact and activated renin-angiotensin system (RAS) may be an important determinant of erythropoiesis in a variety of clinical conditions, including hypertension, chronic renal insufficiency or failure, chronic obstructive pulmonary disease, and congestive heart failure. Accordingly, RAS inactivation may confer susceptibility to the hematocrit-lowering effects of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Indeed, a dose-dependent decrease in hematocrit is observed within the first month of such therapy. In the majority of patients with hypertension decreases in hematocrit values after RAS inactivation are small and not clinically important. In extreme conditions, however, such as erythrocytosis after successful renal transplantation, secondary polycythemia of chronically hypoxemic COPD patients, erythrocytosis associated with renovascular hypertension, severe cardiac or renal failure, the hematocrit-lowering effect of angiotensing-converting enzyme inhibitors and angiotensin receptor blocker may be profound and even lead to or worsen anemia. Hematocrit reachs its nadir value within three months, and then it remains stable during long-term observations. After discontinuation of RAS blockade, hematocrit values rise gradually over the next three to four months towards the pretreatment levels. The mechanism(s) related to this phenomenon is not yet fully understood, but angiotensin II seems to be responsible for inappropriately sustaining secretion of erythropoietin despite hematocrit elevation and capable to directly stimulate the erythroid progenitors in bone marrow to produce erythrocytes.
[Back to top] The Shift in the “Paradigm” of the
Pharmacology of Hypertension
Christodoulos S. Flordellis, Dimitrios Goumenos, George Kourounis, Sotirios A. Tsementzis, Herve Paris and Jaannis Vlachojiannis
Until recently elevated blood pressure was considered as a hemodynamic entity representing an increase in workload for the heart and the arterial tree. Control of hypertension meant hemodynamic unloading, through inhibition of vasoconstrictor pathways, principally renin-angiotensin system and sympathetic system. In recent years however a new pharmacological approach has evolved as a result of (i) the dissociation of endothelial dysfunction and vascular pathology from increased blood pressure; (ii) the recognition that endothelial dysfunction regards not only the vascular reactivity, but also promotes atherosclerosis and thrombosis; and (iii) an improved understanding of the complexity of local-tissue renin angiotensin system and of the vasodilatory and cytoprotective role of natriuretic peptides. This has led to a reconsideration of existing medicines in terms of specification on endothelial function, more rationalized application of drugs and search for new compounds targeting both vasodilatory and anti-proliferative pathways. Examples include b1-adrenergic antagonists, such as Nebivolol and Carvedilol, and vasopeptidase inhibitors, such as Omapatrilat, that inhibit simultaneously the angiotensin converting enzyme and neutral endopeptidase. Furthermore the identification of genetic polymorphisms in the effectors involved in the pathophysiology of hypertension or in the response to anti-hypertensive drugs, such as the p22phox subunit of NADPH oxidase, a-adducin or adrenergic receptors, has promoted the prospective of both better understanding of hypertension and individualized strategies for its treatment.