Synthesis of docosahexaenoic acid derivatives designed as novel PPARγ agonists and antidiabetic agents

Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
Bioorganic & Medicinal Chemistry (Impact Factor: 2.79). 02/2006; 14(1):98-108. DOI: 10.1016/j.bmc.2005.07.074
Source: PubMed


To discover novel peroxisome proliferator-activated receptor gamma (PPARgamma) agonists that could be used as antidiabetic agents, we designed docosahexaenoic acid (DHA) derivatives (2 and 3), which have a hydrophilic substituent at the C4-position, based on the crystal structure of the ligand-binding pocket of PPARgamma. These compounds were synthesized via iodolactone as a key intermediate. We found that both DHA derivatives (2 and 3) showed PPARgamma transactivation higher than, or comparable to, that of pioglitazone, which is a TZD derivative used as an antidiabetic agent. DHA derivatives related to these potent compounds 2 and 3 were also synthesized to study structure-activity relationships. Furthermore, 4-OH DHA 2, which shows strong PPARgamma transcriptional activity, was separated as an optically pure form.

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    • "Furthermore, treatment with PPARγ agonists significantly improves measures of cognition in mild AD and mild cognitively impaired subjects compared to a placebo [48]. PPARγ's are known to bind to and be activated by EPA, DHA, and DHA metabolites [49] [50] [51] and omega- 3 PUFA supplementation has also been shown to reverse age-related decreases in the levels of PPARγ in the aged rat forebrain [41]. There are a number of inflammatory events that occur in the brain as a response to the presence of Aβ. "
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    ABSTRACT: Alzheimer's disease is the most common form of dementia in the elderly and is a progressive neurodegenerative disorder characterised by a decline in cognitive function and also profound alterations in mood and behaviour. The pathology of the disease is characterised by the presence of extracellular amyloid peptide deposits and intracellular neurofibrillary tangles in the brain. Although many hypotheses have been put forward for the aetiology of the disease, increased inflammation and oxidative stress appear key to be features contributing to the pathology. The omega-3 polyunsaturated fats, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have well-characterised effects on inflammation and may have neuroprotective effects in a number of neurodegenerative conditions including Alzheimer's disease. The aims of this paper are to review the neuroprotective effects of EPA and DHA in Alzheimer's disease, with special emphasis on their role in modulating oxidative stress and inflammation and also examine their potential as therapeutic agents.
    International Journal of Alzheimer's Disease 06/2010; 2010(2). DOI:10.4061/2010/274128
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    • ". Indeed, the most likely way to boost the development of drugs based on reported DHA effects in AD will probably be the development of patentable formulations either based on DHA chemical derivatives or on genuine combinations of compounds [63] [64]. In this regard, studies in animal models of AD can be particularly helpful in deciphering the mechanisms of action of DHA that could lead to the development of new potent chemical entities replicating the neuroprotective actions of DHA. "
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    ABSTRACT: Studies in animals clearly show that oral intake of docosahexaenoic acid (DHA) can alter brain DHA concentrations and thereby modify brain functions. This provides us with an opportunity to use DHA as a nutraceutical or pharmaceutical tool in brain disorders such as Alzheimer disease (AD) and Parkinson disease (PD). Most of the published epidemiological studies are consistent with a positive association between high reported DHA consumption or high DHA blood levels and a lower risk of developing AD later in life. Such observations have prompted the investigation of DHA in three different transgenic models of AD. These analyses show that animal models of AD are more vulnerable to DHA depletion than controls and that DHA exerts a beneficial effect against pathological signs of AD, including A beta accumulation, cognitive impairment, synaptic marker loss, and hyperphosphorylation of tau. Multiple mechanisms of action can be associated with the neuroprotective effects of DHA and include antioxidant properties and activation of distinct cell signaling pathways. Although the first randomized clinical assays have yet failed to demonstrate convincing beneficial effects of DHA for AD patients, the knowledge gathered in recent years holds out a hope for prevention and suggests that the elderly and people bearing a genetic risk for AD should at least avoid DHA deficiency.
    Prostaglandins Leukotrienes and Essential Fatty Acids 11/2007; 77(5-6):287-93. DOI:10.1016/j.plefa.2007.10.019 · 2.35 Impact Factor
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    • "[Schrier et al., 2001], the same subtype implicated in primary afferent nociceptive behaviour and it will, therefore, be interesting to examine the affects of DHA on both acute and neuropathic pain states. A significant number of o-3 fatty acid derivatives have already been synthesized around this backbone and, given the abundance of DHA in the human diet, both DHA and its metabolites should prove relatively safe [Itoh et al., 2006] Anandamide Endocannabinoids are highly lipophilic molecules thought to act as retrograde messengers and to protect, in part, against excitotoxicity by modulating neuronal excitability. Anandamide (N-arachidonyl-ethanolamine; Fig. 2) is an endogenous CB1 cannabinoid receptor ligand that mimics many of the psychoactive effects of delta 9 -tetrahydrocannabinol, the most widely recognized active component of marijuana [Lambert and Fowler, 2005]. "
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    ABSTRACT: It has become generally accepted that presynaptic high voltage–activated N-type calcium channels located in the spinal dorsal horn are a validated clinical target for therapeutic interventions associated with severe intractable pain. Low voltage–activated (T-type) calcium channels play a number of critical roles in nervous system function, including controlling thalamocortical bursting behaviours and the generation of spike wave discharges associated with slow wave sleep patterns. There is a growing body of evidence that T-type calcium channels also contribute in several ways to both acute and neuropathic nociceptive behaviours. In the one instance, the Cav3.1 T-type channel isoform likely contributes an anti-nociceptive function in thalamocortical central signalling, possibly through the activation of inhibitory nRT neurons. In another instance, the Cav3.2 T-type calcium channel subtype acts at the level of primary afferents in a strongly pro-nociceptive manner in both acute and neuropathic models. While a number of classes of existing clinical agents non-selectively block T-type calcium channels, there are no subtype-specific drugs yet available. The development of agents selectively targeting peripheral Cav3.2 T-type calcium channels may represent an attractive new avenue for therapeutic intervention. Drug Dev. Res. 67:404–415, 2006. © 2006 Wiley-Liss, Inc.
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