Current Medicinal Chemistry - Cardiovascular & Hematological Agents - Volume 1, Issue 2, 2003

Mouse model systems which allow bone marrow reconstitution can be used to analyse genetically programmed leukemia. The original and most widely used system is that of post 5-fluorouracil mouse hematopoietic stem cells (HSC) into lethally irradiated syngeneic mice. Another more recent system allows analysis of human HSCs in the NODSCID mouse. Both systems are discussed as models for analysis of gene induced leukemia.

1-Azaadamantane (1-azatricyclo [3.3.1.1 3,7]decane) was synthesized in 1953, and the derivatives have been used as rigid models for studies on intramolecular charge transfer phenomena, fluorescence excitation Rydberg states, highly twisted amides, solid electrolyte gas sensors, basicities, and self-organization systems. These structures have also been attracting considerable interest due to their pharmacological activities. The substituted 1- azaadamantanes as conformationally restricted amines have great potential for the therapeutic utilization as anticholinergic agents, serotonergic agents, and squalene synthase inhibitors. However, many steps have been needed for the synthesis of 1-azaadamantanes, and the concise synthetic approaches have been developed. Though double or triple Mannich reactions yield 1-azaadamantanes in moderate yields, the reduction steps are necessary. Our recent research has revealed that trifluoromethanesulfonic anhydride is available for the convenient synthesis of 1-azoniaadamantanes and 1-azaadamantanes without reduction. The new tools for the discovery of novel drugs such as quantitative structure-activity relationship (QSAR) analysis and vibrational circular dichroism (VCD) spectroscopy have also been discussed.

In the last 15 years, calcium channel blockers have been widely used for treating cardiovascular diseases. These agents are a heterogeneous group of drugs with differing cardiovascular effects, and are effective in the treatment of angina and hypertension. These synthetic compounds bind separately with receptor sites located in or near the calcium channel, at molecular sites still to be fully identified.Verapamil, nifedipine and diltiazem are the most representative calcium channel blockers and used as prototypes for the design and development of new anticalcium molecules with potential efficacy and reduced toxic effects.There are three different types of voltage-operated calcium channels (VOCs): L-type, T-type and N-type, which are considered extra-cellular, but some anti-calcium agents as bepridil possess potential intracellular calcium activity. Many synthetic compounds containing heterocyclic ring in their structures have attracted considerable interest since current studies revealed their mechanisms and sites of action.This article reviews the new advances in the calcium channel antagonist group, showing new structures with longer-acting and higher vascular selectivity.

Initiation of thrombus formation involves the platelet adhesion receptors, glycoprotein (GP)Ib-IX-V and GPVI, that bind von Willebrand factor (vWF) and collagen, respectively. These interactions trigger intracellular signals leading to degranulation, elevation of cytosolic Ca2+, cytoskeletal rearrangements, and “inside-out” activation of the integrin, GPIIb-IIIa (αIIbβ3) that binds von Willebrand Factor (vWF) or fibrinogen and mediates platelet aggregation. GPIba (the vWF-binding subunit of GPIb-IX-V) of the leucine-rich repeat protein family and GPVI of the immunoglobulin superfamily not only have a parallel physiological function, but recent studies of these receptors have revealed structureactivity relationships amongst snake venom toxins which target them. Two families of venom proteins, the C-type lectinlike proteins and metalloproteinase-disintegrins, target GPIbα, GPVI and / or the collagen-binding integrin, GPIa-IIa (α2β1). Members of the C-type lectin family interact specifically with GPIba (echicetin, alboaggregin-B, agglucetin), GPVI (convulxin, ophioluxin) or GPIa-IIa (rhodocetin), whereas related proteins accomplish dual receptor occupancy and bind GPVI and GPIba (alboaggregin-A, alboluxin), or GPIbα and GPIa-IIa (aggretin). These latter venom proteins mimic physiological ligands, vWF or collagen, which also recognize more than one receptor. Similarly, metalloproteinasedisintegrin family proteins target GPIbα (mocarhagin, crotalin), GPVI (alborhagin) or GPIa-IIa (jararhagin), resulting in inhibition or induction of platelet aggregation by proteolytically dependent or independent mechanisms. Anti-thrombotics based on snake venom GPIIb-IIIa inhibitors have been investigated clinically, however analogous proteins recognizing GPIb-IX-V or GPVI are yet to be therapeutically exploited.

Diadenosine polyphosphates (ApnA) are naturally occurring molecules which have been identified in human and guinea-pig cardiac tissue and whose physiological role is being established. They are stored in platelet dense granules in a metabolically inactive form. ApnA form a class of dinucleotides, including diadenosine triphosphate (Ap3A), diadenosine tetraphosphate (Ap4A), diadenosine pentaphosphate (Ap5A) and diadenosine hexaphosphate (Ap6A) which have vasopressor actions in some tissues and vasodilator actions in others.ApnA have been reported to interact with receptors distinct from P1 and P2-purinoceptors, and the presence of a unique Ap4A receptor has been demonstrated in isolated ventricular myocytes. Despite the identification of this receptor, other studies suggest that some of the cardiovascular effects are mediated by purinoceptors. ApnA are released from platelet dense granules into the circulation during the platelet release reaction where they can reduce heart rate. The existence of ApnA in myocardial tissue and platelet granules as well as their effects on coronary artery tone and myocardial function suggests a regulatory role for these compounds in the heart.This review describes the effects of ApnA in terms of their coronary vasomotor and cardiac electrophysiological effects. The mechanism responsible for these effects is reviewed; including the involvement of purinergic receptors, the effects of alterations in extracellular pH and the contribution of nitric oxide and prostanoids. Potential pro-arrhythmogenic effects of diadenosine polyphosphates during myocardial ischaemia are also discussed as these compounds could contribute to inhomogeneities of repolarization in ischaemic myocardium.

Platelet-collagen interaction plays an important role in hemostasis and pathological thrombosis. Upon an injury to the subendothelium of a blood vessel wall, platelets attach to the denuded substrate, aggregate, and release biological substances. Many investigators are trying to explore blocking agents to interrupt the adhesion of platelets to the damaged walls. To this date, extensive studies on developing inhibitors for platelet glycoprotein IIb / IIIa have been conducted. There are many trial reports showing that the efficacy of these antagonists has not completely blocked the adhesion of platelets to the distal site(s) of the injury. Type I and type III collagen are present in abundant amounts in blood vessel walls and other laboratories have obtained various active peptides from collagen molecules to block type I and type III collagen-platelet interaction. We have tried to develop active peptides from platelet receptors for types I and III collagen to aberrant both type I and type III collagen-induced platelet aggregation. We have defined effective and specific peptide inhibitors for each type of collagen to block binding to washed platelets, platelet aggregation, and adhesion of washed platelets to rabbit aortic segments.

Capsaicin (8-methyl-N-vannillyl-6-nonenamide), via binding to the vanilloid receptor subtype 1 (VR1), stimulates a subpopulation of primary afferent neurons that project to cardiovascular and renal tissues. These capsaicinsensitive primary afferent neurons are not only involved in the perception of somatic and visceral pain, but also have a “sensory-effector” function. Regarding the latter, these neurons release stored neuropeptides through a calcium-dependent mechanism via the binding of capsaicin to the VR1. A subset of capsaicin-sensitive sensory nerves contains calcitonin gene-related peptide (CGRP) and substance P (SP). These sensory neuropeptides are potent vasodilators and natriuretic / diuretic factors. Neonatal degeneration of capsaicin-sensitive sensory nerves has revealed novel mechanisms that underlie increased salt sensitivity and several experimental models of hypertension. These mechanisms are reviewed, which include insufficient suppression of plasma renin activity and plasma aldosterone levels subsequent to salt loading, enhancement of sympathoexcitatory response in the face of a salt challenge, activation of the endothelin-1 receptor, and impaired natriuretic response to salt loading in capsaicin-pretreated rats. These data indicate that sensory nerves counterbalance the prohypertensive effects of several neuro-hormonal systems to maintain normal blood pressure when challenged with salt loading. Mechanisms underlying pneumotoxicity and pulmonary hypertension as revealed by degeneration of capsaicin-sensitive nerves are also discussed. Finally, the therapeutic utilities of capsaicin, endogenous anandamide, and CGRP agonists are assessed.

Integrins are a family of heterodimeric class I transmembrane receptors, many of which bind to the RGD sequence in adhesive proteins and mediate the adhesive interactions of a variety of cells. The RGD motif has also been found in snake venom proteins that specifically inhibit integrin binding function and serve as potent integrin antagonists. The majority of these proteins interact with β1 and β3 associated integrins and their potency is at least 500-2000 times higher than short RGD peptides. Structural and functional studies suggest that the inhibitory potency of these proteins lies in subtle positional requirements of the tripeptide RGD that is harboured in a defined flexible loop. The integrin-binding specificity and selectivity of each of the proteins is controlled by amino acid residues in this loop in close vicinity to the RGD-motif.The review includes an overview of the structure and function of snake-venom integrin antagonists. The ability of these proteins to control platelet aggregation, cell adhesion and ligand binding is compared to that of short linear, cyclic RGD peptides and RGD-containing proteins and the influence of modulation of amino acid residues flanking the RGD motif is also considered. The review is intended to provide insight into the development of novel inhibitors as drugs.

Food proteins can be a source of various bioactive peptides including such possessing anti-hypertensive activity. While most orally active anti-hypertensive peptides derived from food proteins inhibit the angiotensin Iconverting enzyme (ACE), ovokinin (2-7) (RADHPF), a peptide isolated from a chymotryptic digest of ovalbumin, has been shown to induce nitric oxide-dependent vasorelaxation in an isolated mesenteric artery as well as anti-hypertensive effect after oral administration in spontaneously hypertensive rats (SHRs). Rational amino acid replacement lead to the ovokinin (2-7) analog, RPLKPW, which had the highest anti-hypertensive activity among the tested peptides. Furthermore, oral administration (0.1 mg / kg) of the peptide lowered the blood pressure of SHR but not of normotensive Wistar-Kyoto (WKY) rats. In order to develop a novel use of this potent anti-hypertensive peptide for prevention of hypertension, RPLKPW has been genetically introduced into the homologous sequences in soybean β-conglycinin α'subunit by site-directed mutagenesis. The recombinant RPLKPW-incorporated α' subunit expressed in E. coli has been shown to exert anti-hypertensive activity after oral administration in SHR. Thus, RPLKPW-incorporated α' subunit is the first example of a genetically modified food protein possessing physiological activity based on a bioactive peptide.