Over the past decades,considerable attention had been focused on the development of peripherally acting selective κ-opioid receptor agonists devoid of many side effects associated with μ-agonists and central κ-agonists.In a continuing effort of developing novel κ-opioid receptor agonists,our research group had discovered MB-lc[1],a novel tetrahydroisoquinoline κ-opioid receptor agonist with high affinity and selectivity for κ-receptor(κKi=0.033nM,μKi/κKi=21151).However,we were quite disappointed to note that MB-lc can cause centrally mediated opioid side effects such as sedation and anxiety.