CENTRAL AND PERIPHERAL ANALGESIC AGENTS - CHEMICAL STRATEGIES FOR LIMITING BRAIN PENETRATION IN KAPPA-OPIOID AGONISTS BELONGING TO DIFFERENT CHEMICAL CLASSES

Over the past decade there has been great interest by the pharmaceutic al industry in the development of novel analgesics which act by activa tion of central kappa-opioid receptors. However, in view of the spectr um of unwanted CNS effects associated with such agents, recent efforts have been focused on peripherally-selective compounds with limited ab ility to cross the blood-brain barrier (BBB). In this review, the auth ors consider the chemical strategies and associated synthetic procedur es employed by various research groups to produce hydrophilic compound s with retained kappa-opioid agonist activity. Physico-chemical (clogP , Delta logP) and biological methods (antinociception following admini stration by peripheral and central routes; ex-vivo binding to detect p lasma and brain levels of the drugs) utilized to assess brain penetrat ion are described and compared. Overall, in-vivo ratios correlate bett er-with Delta logP values than with clogP.