Peripheral benzodiazepine receptors (PBRs) are widely distributed throughout the body, but their functions are unknown. They are found on mononuclear phagocytes, and they are up-regulated in a number of neurological and other disease states. We explored the functional consequences of PER ligand binding to mononuclear-derived cells using the high-affinity ligands 1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3- isoquinolinecarboxamide (PK 11195) and 4'-chlorodiazepam (7-chloro-5-(4'-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one; Ro 5-4864). The functions were the following: respiratory burst; secretion of glutamate, interleukin-1 beta (IL-1 beta), and tumor necrosis factor-alpha (TNF-alpha); toxicity of culture supernatants towards SH-SY5Y human neuroblastoma cells; and expression of the inflammatory surface markers HLA-DR and Fc gamma RII (CDw32). PK 11195 inhibited the respiratory burst response, reduced release of glutamate and IL-1 beta, and suppressed secretion of products cytotoxic to neuronal cells. Selectivity was suggested by the failure of PK 11195 to influence TNF-alpha secretion or expression of HLA-DR and CDw32. Powerful ligands of PBRs, such as PK 11195, may be useful inhibitors of selective macrophage functions, retarding both local and systemic inflammation. Since PK 11195 readily enters the brain, it may be beneficial in treating central as well as peripheral inflammatory diseases.