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Corticotropin Releasing Factor (CRF) antagonists are considered promising for treatment of stress-related illnesses such as major depression and anxiety-related disorders. We report here the design, synthesis and biological evaluation of 91 truncated astressin analogues in order to deduce the pharmacophoric amino acid residues. Such truncated peptides may serve as valuable lead structures for the development of new small, non-peptide-based CRF antagonists. N-Terminal truncation of astressin led to active CRF antagonists that are substantially reduced in size and are selectively active at the human CRF receptor type 1 in vitro and in vivo. Subsequently, an alanine scan in combination with further truncated derivatives led to the proposal of a new pharmacophoric model of peptide-based CRF antagonists. It was found that the astressin(27-41)C sequence is the shortest active CRF antagonist. The first eight N-terminal amino acid residues were found to be an important structural determinant and were replaceable by alanine residues, thus enhancing the alpha-helical propensity. A covalent structural constraint is of utmost importance for the preorganization of the C-terminal amino acid residues. The C-terminal heptapeptide sequence, however, was found to be crucial for the antagonistic activity, since substitution or deletion of any residue led to inactive compounds.

In recent publications A2′‐5′A2′‐5′A was found to be an inhibitor of protein synthesis. In this research conformational analysis of the 2′‐5′‐linked nucleotides A2′‐5′A, A2′‐5′A2′‐5′A and A2′‐5′U is reported. The complete 1H‐NMR assignment of the three compounds is given. The degree and mode of base‐base stacking is extracted from coupling constant data and circular dichroic (CD) spectra at various temperatures. The 2′‐5′ nucleotides surprisingly show a much stronger tendency to stack than the 3′‐5′ compounds. At 85°C A2′‐5′A occurs for about 50% in stacked states. The mode of stacking is different from 3′‐5′ ribonucleotides where the sugar rings predominantly adopt an N conformation. A2′‐5′U displays an A(S)2′‐5′U(N) stacked state. In A2′‐5′A ‘mixed’ modes of stacking, i.e. NN, NS, SN and SS, are proposed to account for the CD and NMR observations.

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