Mast cell histamine secretion in response to somatostatin analogues: structural considerations

Comparative studies of the activity of somatostatin and of several of its analogues in releasing histamine from rat mast cells suggest that the integrity of the positively charged amino terminus and of lysines at positions four and nine of somatostatin may be necessary to preserve its histamine releasing activity. D-Lys4 substitution reduced activity by 80% while D-Lys9 substitution increased it four fold. Replacement of the amino terminal Ala by Tyr or simultaneous removal of Ala1,Gly2 and the amino portion of the now terminal Cys3 inhibited the activity by about 95%. Finally, dihydrosomatostatin retained 33% activity while an analogue where both Cys sulfur atoms were permanently blocked by acetamidomethyl groups retained only about 13% activity. Using information from these studies and from the literature, two-dimensional and space-filling models approximating the conformation of somatostatin were constructed and compared with a plausible corresponding model of the hexameric form of 48/80, the most active congener of this classic mast cell secretagogue. By such modelling it was possible to show that the orientation of the cationic moieties in the two molecules could be similarly arranged thereby perhaps explaining the ability of these compounds to induce mast cell secretion.