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3 kJ/mol). It seems reasonable that the curine alkaloids may compete with the natural substrates for these protein targets and serve as leads in designing and developing more potent and selective drugs against T. brucei.The cyclic dimeric peptide 1229U91 (GR231118) has an unusual structure and displays potent, insurmountable antagonism of the Y1 receptor. To probe the structural basis for this activity, we have prepared ring size variants and heterodimeric compounds, identifying the specific residues underpinning the mechanism of 1229U9