ABSTRACT
Considerable advances in the fields of molecular biology and pain research during the last decade has led to the identification of a wide range of pharmacological targets for new analgesics. Genes of interesting targets may be regulated either upwards or downwards under pathophysiological, i. e. inflammatory or neuropathic pain conditions. Targets exclusively expressed in terms of tissues relevant for pain transmission, are potential promising candidates for the generation of analgesics devoid of serious side-effects. Especially those targets that are expected to be essential for the development and maintenance of a number of pains offer the opportunity to define courses of treatment for patients with a variety of different symptoms and causes. Modern drug-development is based on the identification of compounds directed against these specific targets. In a high throughput screening procedure, all substances of our drug library (about 1 million) are examined for their effects on this specific molecular mechanism. Predicted pain-relieving effects are then identified by a screening cascade where selected drugs are tested for their activity in in-vitro assays on isolated neurons, tissues or recombinant cell lines. The final validation of a drugs' antihyperalgetic or antiallodynic properties is carried out in the relevant animal models of chronic pain, which mirror the clinical situation as much as possible. Compounds being more efficient or having an improved side effect profile in these models than medications currently available (and which are toxicologically harmless) are interesting candidates for clinical development.
Subject(s)
Analgesics/therapeutic use , Pain/drug therapy , Acute Disease , Analgesics/adverse effects , Chronic Disease , Drug Evaluation, Preclinical , Drug Industry , Germany , Humans , Inflammation/complications , Inflammation/pathology , Pain/physiopathologyABSTRACT
Several prenylphenols from basidiocarps of European and Chinese Albatrellus spp., namely grifolin (1), neogrifolin (2), confluentin (3), scutigeral (4), and albaconol (5) were investigated concerning their activities in test models for vanilloid receptor modulation. The isolation of these compounds from A. confluens and structure elucidation of the novel natural product confluentin (3) are described. The effects of scutigeral and neogrifolin on vanilloid receptors were studied by means of electrophysiological methodology on rat dorsal root ganglion neurons as well as on recombinant cell lines expressing the rat VR1 receptor. Concurrently, the effects of compounds 1-5 on a reporter cell line expressing the human vanilloid receptor VR1 were measured. In contrast to previous studies reported in the literature, the results of these investigations suggest that fungal prenylphenols act as weak antagonists (activity in the microM range), rather than exhibiting agonistic activities.
