Current Medicinal Chemistry - Volume 9, Issue 17, 2002

Developments in the domain of non-peptide opioid receptor agonists, beginning from the first evidence of opiate binding to definite receptors, are briefly summarized. The recent achievements are in a more detailed way depicted and discussed.Novel agonists for each of three opioid receptor basic types (δ, κ and μ) are presented with the special emphasis on one-type-selective ligands. Such selective or even specific agonists have been synthesized with a moderate success. Considerably more serious difficulties concern searching for selective ligands for opioid receptor subtypes (μ1, μ2, δ1, δ2, κ1, κ2, κ3) which may be connected with the fact that dissimiliarities observed in vivo result from postbinding processes (signaling).For the large number of opioid receptor ligands, their structural diversity and relative easiness of generating them from combinatorial libraries (not comparable even with that of orphanine receptors) it is justified to consider the plasticity of opioid receptors (μ-receptor especially). This remark, in conjunction with the existence of opioid receptor types and subtypes, may enable to create new drugs with significantly reduced side-effects.The above facts and brand new reports about highly-active opioid agonists possessing no moieties thought to be essential for agonist activity make the need of reevaluation of classical opioid receptor pharmacophore model extremely important.In general, research results suggest that selective agonists of opioid receptors can be found both in morphine type of ligands and new structures like pyrido-acridine derivatives (COMP1) or diphenylmethylpiperazine derivatives (SNC 80). Better understanding of the structural prerequisites of the opioid receptors binding domains will certainly lead to even more potent and more selective ligands in a near future.

This paper is the second part of the review on opioid receptor ligands and deals with the progress in the field of non-peptide opioid receptor antagonists (starting from the pioneering opiate studies in the early seventies) with particular stress on the last decade accomplishments.As X-ray high resolution structure determination of the ligand-receptor systems for G protein-coupled receptors meets with considerable experimental obstacles, the knowledge about ligand interactions with the membrane-bound receptors traditionally derives from structure-activity studies. Hence, such a concise summary, collecting chemically distinct but pharmalogically relative compounds, may be a convenient information source for any research concerning ligand-opioid receptor binding or rational drug design.

Oxidative damage is shown to affect every class of biological macromolecule in Alzheimer disease. Disruptions in iron and copper homeostasis are understood as being key players in neurodegenerative disease pathogenesis. Metal homeostasis as it pertains to alterations in brain function in neurodegenerative diseases is reviewed here with its relations to oxidative stress. While there is substantial documented evidence for alterations in transition metal metabolism, redox-activity and localization, it is also important to note that alterations in specific copper- and iron-containing metalloenzymes also contribute to the neurodegenerative process. Understanding these changes offers the opportunity to identify pathways where modification of the disease process can offer effective clinical intervention, from gene therapy to pharmaceuticals with antioxidant and chelating properties.

Cisplatin represents one of the most potent drugs available in the cancer chemotherapy for several solid tumors, such as germ cell tumors, ovarian, lung, head and neck, and bladder cancers. Structure-activity relationship studies showed that leaving groups (generally chlorine) and two amine ligands in platinum complexes must be in the cis orientation and that the corresponding trans compounds are inactive. During the 1990's, several groups have reported trans-platinum compounds with in vitro growth inhibitory and in vivo antitumor properties. Some of these complexes were active against tumor cells resistant to cisplatin. More interestingly, there is a difference in cellular and biochemical pharmacology between trans-platinum complexes and cisplatin. Thus, monofunctional adducts might be related to the cytotoxicity of the trans-platinum-iminoether compounds against cis-DDP sensitive / resistant cell lines, unusual structure of long-range interstrand cross-links might be relevant for great effectivity of bifunctional polinuclear trans-platinum(II) compounds against cis-DDP resistant variants. Transplatinum compounds, appear to follow different pattern of cell killing in comparison to cisplatin, thus giving a reason for optimism in their development as a new class of platinum-based antitumor drugs.

Recent advances in growth factor therapy for the treatment of ischemic disease of the heart and peripheral vasculature offer hope for a novel strategy that is based on the generation of a new blood supply. Members of the fibroblast growth factor and vascular endothelial growth factor families and several other molecules have all been shown to induce significant angiogenesis in animal models of acute or chronic, myocardial or peripheral ischemia. In addition, it is known that arteries from specific regions in the arterial tree have various developmental origins. This may be one explanation for why arteries of different parts of the arterial tree undergo differential changes during the pathogenesis of vascular disease. There is speculation over several fundamental questions concerning the origin of vessel wall cells and the mechanisms that regulate their development and differentiation.Here we discuss what is known to date about the differential developmental origin of arteries and the possible consequences for therapeutic angiogenesis.

A variety of hydroxamic acid derivatives have recently been touted for their potential use as inhibitors of hypertension, tumor growth, inflammation, infectious agents, asthma, arthritis, and more. Here we provide a comprehensive review of the basic medicinal chemistry and pharmacology of hydroxamic acid derivatives that have been examined as inhibitors of zinc metalloproteases, matrix metalloproteinases, leukotriene A4 hydrolases, ureases, lipoxigenases, cyclooxygenases, as well as peptide deformilases.