Dr Bernard Roques - 2003

"A Race in the Opioid Pathway!"
Dr Bernard Roques
Professor, Vice-President & Scientific Director
PharmaLeads, Paris, France

The discovery that the endogenous opioids, enkephalins are very small peptides has been a «graal» for various disciplines. This resulted in a rush to peptide synthesis and studies of metabolizing enzymes. Thus, the physiological roles of enkephalins and its relationships with other neurotransmitters, including cholecystokinin was achieved by modulating their neuronal tonic or phasic release with peptidases inhibitors. Among these compounds, Tiorfan®, is so far the single pharmaceutical compound issuing directly from the enkephalin story. Much more potent inhibitors acting in the various inactivating metallopeptidases (neprilysin or NEP , APN) sometimes able to block also the formation of hyperalgesic substances like L TB4 deriving from LTA4 hydrolase have been designed. In addition to their possible use as new analgesics able to fit the gap between opiates and NSAIDs, these inhibitors have been used to investigate the crucial role of the endogenous enkephalins in the DA-dependent reward system. New concepts on inter-relationships between neuropeptides in addictive process have merged from the use of inhibitor-induced modulation of endogenous neuropeptides and receptor knockout mice.