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제목: Multifuctional peptide ligands for the treatment of pain
연사: 이연선 박사
Department of Chemistry, University of Arizona, Tucson, AZ 85721

일시: 2008년 9월 19일 오후 5시
장소: 302동 708호
문의: 880-8802/김영규교수/정밀화학실험실

 Abstract

Morphine is one of the most important drugs for the treatment of pain, even though its long-term administration is accompanied by serious side effects such as constipation, tolerance, and dependence, features shared by drugs from the opioid class. Many studies have shown that Cholecystokinin (CCK), Nerurokinin (NK), and melanocortin (MC) receptors are involved in the modulation of nociception and function as anti-opioids and pain can be controlled by blockade of the receptors due to functional interactions with the opioid system. From this background, we have hypothesized that the development of novel multifunctional ligands, which possess properties of antagonists at CCK and/or MC receptors, and of agonists at the opioid receptors, within the same molecule may present a significant therapeutic advantage in the treatment of pain states and enhanced analgesic effect in chronic pain states without the development of tolerance.

For the purpose of design, we took a novel approach in which a template for one receptor will be fused (or overlapped) with one for the others to create a chimera so that the designed ligands maintain topologically related structures to their respective pharmacophores. Considering their respective topological structures, different combinations of multifunctional ligands were designed and synthesized by standard SPPS using Fmoc chemistry under microwave and/or LPPS using Boc chemistry stepwise. The multifunctional ligands showed moderate to high in-vitro binding affinities at the all receptors with suitable functional activities. Some ligands showed very good anti-hyperalgesic and anti-allodynic effects in in-vivo tests. From the biological profile it was demonstrated that it is reasonable to build agonist function for opioid receptors and antagonist function for CCK and/or MC receptors in a single structure. It is worth noting that different pharmacophores for different G-protein coupled receptors (GPCRs) can be designed into one structure by rational design.

Design considerations and structure-activity relationships will be discussed in detail along with in-vivo assay results. This work was supported by grants from National Institute on Drug Abuse (DA12394 and DA06284).