Contents
Focus on Cannabinoids and Endocannabinoids
Guest Editor: Didier M.
Lambert
Editorial Pp.1359-1359
Current Knowledge on the Antagonists and
Inverse Agonists of Cannabinoid Receptors Pp.1361-1394
Recent Developments in the Medicinal
Chemistry of Cannabimimetic Indoles, Pyrroles and Indenes Pp.1395-1411
Endocannabinoid-Related Enzymes as Drug
Targets with Special Reference to N-Acylphosphatidylethanolamine-Hydrolyzing
Phospholipase D Pp.1413-1422
General Articles
New Medium Oxacyclic O,N-Acetals and
Related Open Analogues: Biological Activities Pp.1423-1438
Congestive Heart Failure: Pharmacological
Agents and the Potential of Btype Natriuretic Peptide Pp.1439-1447
Dual Antagonists of Integrins Pp.1449-1466
Abstracts
[Back to top] Editorial
Five years ago, a special issue of Current Medicinal Chemistry was published (Curr. Med. Chem., 1999, volume 6 issue number 8) and devoted to the “new trends in cannabinoid receptor ligands”. In the preface, the diversity in terms of chemical structures of cannabinoid ligands was highlighted. Five years later, the diversity is more present than ever. The number of compounds reported to act at the endocannabinoid system is impressive, the number of papers devoted to the cannabinoid targets is increasing.
Up to date, two cannabinoid, G-protein coupled, receptors are unambiguously identified and characterised. The degradating processes involve a putative anandamide uptake protein as well as hydrolysing enzymes, two among these are also highly characterised : the fatty acid amide hydrolase and the monoacylglycerol lipase. They could constitute attractive targets and they were the subject of numerous reviews these two last years. Less has been written about the endocannabinoids synthesizing enzymes.
This second special issue devoted to the cannabinoids is divided in three chapters :
The first one, entitled “Endocannabinoid-related Enzymes as Drug Targets with Special Reference to NAcylphosphatidylethanolamine-hydrolyzing Phospholipase D” written by Natsuo Ueda, Yasuo Okamoto and Kazuhito Tsuboi, gives an overview on the endocannabinoid system with an emphasis on the enzymes and more specially to the recently cloned anandamide synthesizing enzyme
The second chapter “Recent Developments in the Medicinal Chemistry of Cannabimetic Indoles, Pyrroles and Indenes” by J. W. Huffman and L. W. Padgett, gives a comprehensive review of this interesting family of cannabinoid ligands.
Finally, the last part is devoted to the “Current Knowledge on the Antagonists and Inverse Agonists of Cannabinoid Receptors” by G.G. Muccioli and D. M. Lambert. This chapter represents a review of the current scientific update of molecules presented in the scientific papers as well as in the patents. It describes antagonists and inverse agonists of both types of cannabinoid receptors and ends to the open field of the putative new cannabinoid receptors antagonists/inverse agonists.
[Back to top] Current Knowledge on the Antagonists and
Inverse Agonists of Cannabinoid Receptors
Ten years elapsed since the discovery by Sanofi of SR141716A the first selective CB1 cannabinoid receptor antagonist. Shortly after, Sanofi also reported the synthesis of the first selective CB2 cannabinoid receptor antagonist, SR144528. Since these two milestones in the cannabinoid field, many other compounds, more or less related to the Sanofi compounds, or based on a completely different scaffold appeared. Several of these compounds are currently involved in clinical trials for diseases such as obesity, nicotine and alcohol addictions, or allergies. Further, the cannabinoid receptors knock-out mice production strengthened the hypothesis of the existence of several other “cannabinoid” receptors for which the first antagonists begin to appear. The large amount of patents taken by many different pharmaceutical companies prove, if necessary, the great therapeutic potential expected for the cannabinoid receptors antagonists.
[Back to top] Recent Developments in the Medicinal Chemistry
of Cannabimimetic Indoles, Pyrroles and Indenes
During the development of new nonsteroidal anti-inflammatory agents, it was discovered that 1-aminoalkyl-3-aroylindoles have affinity for the cannabinoid brain (CB1) receptor. This has led to the development of over 100 cannabimimetic aminoalkylindoles, and the development of SAR for these compounds. Later work demonstrated that the aminoalkyl moiety was not necessary, and could be replaced by a four- to sixmembered alkyl chain without loss of affinity. Investigation of these indoles led to the discovery of a CB2 selective ligand, 3-(1-naphthoyl)-N-propylindole. Subsequent work has provided several additional CB2 selective indoles. On the basis of a proposed pharmacophore for the cannabimimetic indoles, a series of pyrroles and indenes were developed, some of which are potent cannabinoids. SAR for several series of pyrroles have been developed. Two groups have described cannabimimetic indenes, which have been employed as rigid models for the receptor interactions of cannabimimetic indoles with the CB1 receptor. There is some evidence that the indoles bind to a somewhat different site on the receptor than traditional cannabinoids, and interact with the receptor primarily by aromatic stacking.
[Back to top] Endocannabinoid-Related Enzymes as Drug
Targets with Special Reference to N-Acylphosphatidylethanolamine-Hydrolyzing
Phospholipase D
Anandamide (N-arachidonoylethanolamine) is the first discovered endocannabinoid (endogenous ligand of cannabinoid receptors). In animal tissues, anandamide is principally formed together with other bioactive long-chain N-acylethanolamines from membrane glycerophospholipid by two enzyme reactions. The first reaction is the transfer of a fatty acyl chain from the sn-1 position of glycerophospholipid to phosphatidylethanolamine by calcium-dependent N-acyltransferase, resulting in the generation of Nacylphosphatidylethanolamine (NAPE). The second reaction is catalyzed by a phosphodiesterase of the phospholipase D (PLD)-type, which releases N-acylethanolamines from their corresponding NAPEs. The produced N-acylethanolamines are hydrolyzed to fatty acids and ethanolamine by fatty acid amide hydrolase or an amidase acting exclusively at acidic pH. Our recent cDNA cloning of the NAPE-hydrolyzing PLD (NAPEPLD) from mouse, rat and human revealed that NAPE-PLD is a novel enzyme which has no homology with any known PLD enzymes, but belongs to the zinc metallo-hydrolase family of the b-lactamase fold. The recombinant enzyme hydrolyzed various NAPEs, including the anandamide precursor Narachidonoylphosphatidylethanolamine at similar rates, but was inactive with phosphatidylcholine and phosphatidylethanolamine. Considering cannabimimetic activities of anandamide, the enzymes involved in the biosynthesis and degradation of anandamide, including NAPE-PLD, may be promising targets for therapeutic agents.
[Back to top] New Medium Oxacyclic O,N-Acetals and
Related Open Analogues: Biological Activities
Attention is increasingly being focussed on the cell cycle and apoptosis as potential targets for therapeutic intervention in cancer. Taking 1-[(2-oxepanyl)]-5-fluorouracil previously prepared by us, we committed ourselves to increase the lipophilicity of this upper cyclohomologue of Ftorafur and prepared a series of bioisosteric benzannelated seven-membered 5-FU O,N-acetals to test them against the MCF-7 human breast cancer cell line. Benzo-fused seven-membered O,O-acetals or their acyclic analogues led to the expected 5-FU O,N-acetals (or aminals), in addition to six- and to 14- membered aminal structures and acyclic compounds. All the cyclic aminals provoked a Go/G1-phase cell cycle arrest, whereas Ftorafur, a known prodrug of 5-FU, and 1-[2-(2-hydroxymethyl-4-nitrophenoxy)-1-methoxyethyl]-5-fluorouracil (51) induced an S-phase cell cycle arrest. Although breast cancer is most often treated with conventional cytotoxic agents it has proved difficult to induce apoptosis in breast cancer cells and, consequently, improved clinical responses may be obtained by identifying therapies that are particularly effective in activating apoptosis. 1-(2,3- Dihydrobenzoxepin-2-yl)-5-fluorouracil (26) may be particularly useful in stimulating apoptosis in breast cancer. This compound is more potent as an apoptotic inductor than paclitaxel (Taxol®). Finally, a fact that is worth emphasizing is that the cyclic and acyclic 5-FU O,N-acetals induce neither toxicity nor death in mice after one month’s treatment when administered intravenously twice a week, with a 50 mg/kg dose each time. Taken together, the experimental findings provide evidence of specific anti-tumour activity of these new substances and warrant further evaluation in in vivo models of breast cancer to future clinical applications.
[Back to top] Congestive Heart Failure: Pharmacological
Agents and the Potential of Btype Natriuretic Peptide
Congestive heart failure (CHF) is a life-threatening cardiovascular disease that is increasing in prevalence. It is a common cause of death and is accompanied by high direct and indirect costs for treatment. The current situation faced by patients and the medical community with regard to this ailment is one of high mortality, repeated hospitalizations, and combination therapies. The various classes of pharmacological agents that are currently used for patients suffering from CHF include angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), aldosterone antagonists, beta-blockers, calcium channel blockers (CCBs), digitalis drugs, diuretics, inotropic agents, nitrates, and vasodilators. While these agents are all important therapeutic tools in the treatment of CHF, the prognosis for patients with CHF remains poor. Thus improvement of the current pharmacological armamentarium is greatly needed. An endogenous peptide, B-type natriuretic peptide (BNP), has been increasingly utilized in the setting of acute CHF since its approval in 2001. This peptide, or a derivative thereof, has great potential for the treatment of patients at various stages in the progression of heart failure. This review provides an overview of current pharmacological strategies in CHF and addresses potential future developments in the use of BNP for the treatment of CHF.
[Back to top] Dual Antagonists of Integrins
The roles of integrins in pathologies have been studied intensively and only partially explained. This has resulted in the development of several nanomolar antagonists to certain integrins. In most cases, the aim was to produce compounds which are highly selective towards specific integrins. This paradigm has recently shifted a little. Targeting two or more integrins with one compound has become a very attractive concept, especially since it has become clear that several severe disorders, such as pathological angiogenesis, cannot be treated just with highly specific integrin antagonists. This review is aimed to elucidate some aspects regarding the design of drugs with dual activity towards integrins. Integrin structure and tissue distribution will first be described, in order to provide the basis for their functions in various pathologies which will follow. Inhibitors of several pairs of integrins will be described.