Synthetic analogues of oxytocin: an approach to problems of hormone action.

Abstract

Synthetic organic chemistry has in recent years become a recognized participant in the study of hormone action. Although the synthetic approach is capable of yielding copious information about the relation between chemical structure and biological activity and thereby, in principle, it can aid in exploring the molecular basis of hormone action, the results obtained by this approach are by no means unambiguous. For one thing, the great conformational flexibility of peptide chains makes it difficult to estimate the overall effect of a change in chemical structure on the topochemistry of the molecule in that conformation which it adopts in its interaction with a particular receptor site. Furthermore, the complexity of biological systems capable of showing a response to the hormones or their analogues is such that this response cannot, as yet, be confidently interpreted in terms of molecular interactions. A generalized scheme of hormonal regulation in the intact organism is shown in figure 5; an exogenously introduced hormonal peptide will bypass the stages of biosynthesis and release (though it might conceivably operate feedback mechanisms where these exist), but its behaviour in each subsequent stage of the system will be affected by its chemical and physical properties. Any change in the structure of the peptide is therefore likely to modify its interactions at several or all of these stages and the change in overt response will represent the complex results of these modified interactions. To some extent the effect on the individual stages can be distinguished by working with biological preparations of varying complexity, from the whole organism to isolated tissues; but even the simplest tissue preparations are still biochemically very complicated systems in which the receptor molecules have yet to be identified. On the other hand, any stage of the whole process of hormonal regulation is a fair target for attempts to achieve modified biological properties by structural variations, and this paper will be concerned with illustrating these possibilities, using examples from our work on neurohypophysial hormone analogues.