The proportion of older people continues to grow worldwide, especially in developing countries. Non-communicable diseases are fast becoming the leading causes of disability and mortality, and in coming decades health and social policy-makers will face tremendous challenges posed by the rapidly changing burden of chronic diseases in old age. Chronic disease and most oral diseases share common risk factors. Globally, poor oral health amongst older people has been particularly evident in high levels of tooth loss, dental caries experience, and the prevalence rates of periodontal disease, xerostomia and oral precancer/cancer. The negative impact of poor oral conditions on the quality of life of older adults is an important public health issue, which must be addressed by policy-makers. The means for strengthening oral health programme implementation are available; the major challenge is therefore to translate knowledge into action programmes for the oral health of older people. The World Health Organization recommends that countries adopt certain strategies for improving the oral health of the elderly. National health authorities should develop policies and measurable goals and targets for oral health. National public health programmes should incorporate oral health promotion and disease prevention based on the common risk factors approach. Control of oral disease and illness in older adults should be strengthened through organization of affordable oral health services, which meet their needs. The needs for care are highest among disadvantaged, vulnerable groups in both developed and developing countries. In developing countries the challenges to provision of primary oral health care are particularly high because of a shortage of dental manpower. In developed countries reorientation of oral health services towards prevention should consider oral care needs of older people. Education and continuous training must ensure that oral health care providers have skills in and a profound understanding of the biomedical and psychosocial aspects of care for older people. Research for better oral health should not just focus on the biomedical and clinical aspects of oral health care; public health research needs to be strengthened particularly in developing countries. Operational research and efforts to translate science into practice are to be encouraged. WHO supports national capacity building in the oral health of older people through intercountry and interregional exchange of experiences.

The neuropeptidase glutamate carboxypeptidase II (GCPII) hydrolyzes N-acetyl-L-aspartyl-L-glutamate (NAAG) to liberate N-acetylaspartate and glutamate. GCPII was originally cloned as PSMA, an M(r) 100,000 type II transmembrane glycoprotein highly expressed in prostate tissues. PSMA/GCPII is located on the short arm of chromosome 11 and functions as both a folate hydrolase and a neuropeptidase. Inhibition of brain GCPII may have therapeutic potential in the treatment of certain disease states arising from pathologically overactivated glutamate receptors. Recently, we reported that certain urea-based structures act as potent inhibitors of GCPII (J. Med. Chem. 2001, 44, 298). However, many of the potent GCPII inhibitors prepared to date are highly polar compounds and therefore do not readily penetrate the blood-brain barrier. Herein, we elaborate on the synthesis of a series of potent, urea-based GCPII inhibitors from the lead compound 3 and provide assay data for these ligands against human GCPII. Moreover, we provide data revealing the ability of one of these compounds, namely, 8d, to reduce the perception of inflammatory pain. Within the present series, the gamma-tetrazole bearing glutamate isostere 7d is the most potent inhibitor with a K(i) of 0.9 nM. The biological evaluation of these compounds revealed that the active site of GCPII likely comprises two regions, namely, the pharmacophore subpocket and the nonpharmacophore subpocket. The pharmacophore subpocket is very sensitive to structural changes, and thus, it appears important to keep one of the glutamic acid moieties intact to maintain the potency of the GCPII inhibitors. The site encompassing the nonpharmacophore subpocket that binds to glutamate's alpha-carboxyl group is sensitive to structural change, as shown by compounds 6b and 7b. However, the other region of the nonpharmacophore subpocket can accommodate both hydrophobic and hydrophilic groups. Thus, an aromatic ring can be introduced to the inhibitor, as in 8b and 8d, thereby increasing its hydrophobicity and thus potentially its ability to cross the blood-brain barrier. Intrathecally administered 8d significantly reduced pain perception in the formalin model of rat sensory nerve injury. A maximal dose of morphine (10 mg) applied in the same experimental paradigm provided no significant increase in analgesia in comparison to 8d during phase 1 of this pain study and modestly greater analgesia than 8d in phase 2. These urea-based inhibitors of GCPII thus offer a novel approach to pain management.

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