Vasopressin and other
neurohypophyseal peptides affect various processes related to memory and/or learning. A single
subcutaneous injection of
vasopressin increases resistance to extinction of a pole-jumping avoidance response in rat. This test system has been applied in an attempt to relate structural aspects of
neurohypophyseal peptides, analogues, and derivatives with truncated sequences to their effects on conditioned behavior. Thus far it can be concluded that there are more stringent requirements on certain residues in the 20-member covalent ring than in positions 8 and 9 of the linear
peptide portion for
neurohypophyseal hormones to be active. Critical are the contributions of residues in positions 2, 3, and 5; these results are reminiscent of those from conformation-activity correlations of the endocrine effects of
neurohypophyseal hormones, in which the side chain of the residue in position 3 is critical for receptor binding and the side chains of residues in positions 2 and 5 are key for the activation of the receptor. Chemical modifications in position 4 yield analogues that are active and inactive in increasing the resistance to extinction of the avoidance response, depending on the particular structural substitution, similar to results from structure-activity studies of the endocrine activities of
neurohypophyseal hormones. Because behavioral activities of
vasopressin are more tolerant than endocrine activities to modifications of the
hormone in positions 8 and 9, analogues with the most striking dissociation of potencies in learned behavior and endocrine responses are expected to be those with sequence alterations in the linear
peptide portion.
Peptides with linear part sequences of
neurohypophyseal hormones showed little or no activity. The results obtained in this structure-activity study are compared with those of an earlier study in which the ability of various
neurohypophyseal peptides to attenuate
puromycin-induced
amnesia in mice was evaluated.