Effective Mast Cell Degranulating Peptide Inhibitors of the IgE/FceRI Receptor Interaction Abstract: Previous studies with mast cell degranulating (MCD) peptide have shown that peptide [Ala¹²]MCD 8 was an inhibitor of IgE binding to mast cell recep- tors. In an attempt to produce increased inhibition, analogs were synthesized that maintained the ala- nine residue in position 12 in the MCD peptide sequence and were further modified at both ter- mini. Analogs modified at the C-terminus were [Ala¹²,desLys²¹]MCD 2 and [Ala¹²,D-Lys²¹]MCD 4. N-terminus modifications were [desLys⁶Arg⁷ His⁸,Ala¹²]MCD 1, [Ala⁶, Ala¹²]MCD 6, and [Val⁶, Ala¹²]MCD 7. To assess the role of the Proline¹², analogs [D-Ala¹²]MCD 3 and [Meleu¹²]MCD 5 were also synthesized. The analogs were tested for bind- ing to the IgE receptor in cultured mast cells. Inhibi- tory activity of IgE-caused degranulation was measured using a b-hexosaminidase assay. Circular dichroism (CD) and molecular modeling of selected analogs were used to follow possible structural dif- ferences among these analogs. All analogs showed binding affinity to the IgE receptor and inhibition of IgE-induced mast cell degranulation at different levels. Differences in inhibition were most likely because of diverse interactions of the analogs with the receptor as inferred by the CD and modeling studies. Based on the results of the b-hexosamini- dase assay, analog [Val⁶, Ala¹²]MCD 7 proved to be an excellent inhibitor of IgE-mediated mast cell degranulation.