ICI 204448: a kappa-opioid agonist with limited access to the CNS.

1. A number of compounds were evaluated in an attempt to identify a kappa-opioid receptor agonist with limited access to the central nervous system. 2. Quaternary derivatives of the kappa-opioid agonists tifluadom, U-50488H and ethylketocyclazocine were essentially devoid of opioid activity in a range of isolated tissue preparations. 3. A novel compound - ICI 204448 - is described which produced a potent and naloxone-reversible inhibition of electrically-evoked contraction of the guinea-pig ileum, mouse vas deferens and rabbit vas deferens preparations. ICI 204448 was shown to displace the binding of the kappa-opioid ligand [3H]-bremazocine from guinea-pig cerebellum membranes. 4. Ex vivo binding studies in mice showed ICI 204448 to be well absorbed following subcutaneous administration. The brain levels achieved by ICI 20448 were substantially lower than those produced by kappa-agonists such as U-50488H and tifluadom. 5. A good correlation was found for a range of opioids between lipophilicity and degree of CNS penetration.