Bradykinin (BK), synthesized following many pathological insults, causes smooth muscle contraction, increased vascular permeability and stimulation of neuronal pain receptors, actions generally mediated through B2 receptors. In some animal disease models, there appears in vascular smooth muscle a different receptor, on which des-Arg9-BK, normally an inactive BK metabolite, is an agonist. Evidence suggests that interleukin-l (IL-l), a cytokine, is responsible for inducing these B1 receptors. Similarly, in several models of human pathology, and in tissue from patients with diseases thought to be mediated by overproduction of IL-l, BK responsiveness is dramatically increased. Moreover, if healthy tissue is treated with IL-l, responses to BK increase. Thus, IL- l sensitizes tissues to the action of BK and may do so through induction of B1 receptors. NOVA is currently developing BK antagonists based on screens of B2 receptors. The B1 receptor (induced by IL-l), however, may be more important in several inflammatory diseases. Thus, another potentially very important approach may be development of an IL- 1 inhibitor, and provide a novel therapeutic approach to treating inflammatory diseases. This Phase I proposal seeks support for the elucidation of IL-l's role in increasing tissue responsiveness to BK, and in particular its role in inducing B1 receptors. It also seeks support to develop a program to identify nonpeptide IL-l antagonists/inhibitors. Methods will include biochemical and isolated tissue studies, as well as whole animal experiments. Compounds will be selected from NOVA's current directory of chemicals. Agents having IL-l inhibitory activity will provide lead structures to initiate synthetic efforts in Phase II.
