Somatostatin analogues and multiple receptors: possible physiological roles.

The availability of transfected cell lines expressing the five cloned somatostatin receptors has allowed extensive families of synthetic analogues to be screened for their binding affinities to these receptors. Cyclic octapeptides in the octreotide series have high affinity for sstr2 and low affinity for sstr1 and sstr4. Modifications to these analogues can have profound effects on their residual affinity for sstr3 and sstr5. Several linear peptides, incorporating the critical core-D-Trp-Lys-sequence of all active analogues, exhibit selectivity for either sstr3, sstr5 or both, but little affinity for the other three. From these analogues we have assembled a panel of compounds with a useful degree of specificity for sstr2, sstr3 and sstr5 and these have been used to evaluate receptor involvement in various physiological processes. Inhibition of pituitary growth hormone release correlates completely with sstr2 affinity and it appears from preliminary results that inhibition of pancreatic glucagon release is also sstr2 mediated. Effects on gastric acid secretion show a high degree of dependence on sstr2 affinity. Inhibition in vivo by somatostatin of insulin release, amylase release and binding to rat pancreatic acinar cells is highly correlated with sstr5 receptor affinity. Gastric smooth muscle cells have particularly high affinity for sstr3 receptor ligands. The availability of receptor-specific ligands is proving to be of great value in elucidating the physiological roles of each receptor. It is anticipated that these and future generations of analogues will have distinct therapeutic advantages over somatostatin itself and presently available cyclic octapeptides.