Molecular Organization of Receptors : Efficacy, Agonists, and Antagonistsa

Stepwise modification of a conformationally stabilised analogue of the fragment of somatostatin which had been thought to be essential biologically active moiety has enabled us to synthesise the analogue H-(D) Phe-Cys-Phe-(D) Trp-Lys-Thr-Cys-Thr(ol) code-named SMS 201-995, which in vitro is three times more potent than the native hormone in inhibiting the secretion of growth hormone, which is highly resistant to degradation by pure enzymes and by tissue homogenates, which in vivo in rat and rhesus monkey is (depending on test system) at least 20 times more active than somatostatin, which is much longer acting, and which moreover in both species is much more selective in inhibiting the secretion of growth hormone than that of insulin. The compound is active by several routes of administration including the oral, is well tolerated both in laboratory animals and in man, and is currently undergoing preliminary clinical trial.

alpha-Melanocyte-stimulating hormone (alpha-MSH) reversibly darkens frog skins by stimulating melanosome movement (dispersion) within melanophores. Heat-alkali treatment of alpha-MSH results in prolonged biological activity of the hormone. Quantitative gas chromatographic analysis of the hydrolyzed heat-alkali-treated peptide revealed partial racemization particularly at the 4(methionine) and 7(phenylalanine) positions. [Nle4]-alpha-MSH, a synthetic analogue of alpha-MSH, reversibly darkens frog skins and also exhibits prolonged activity after heat-alkali treatment. Synthesis of [Nle4, D-Phe7]-alpha-MSH provided an analogue with prolonged biological activity identical to that observed with heat-alkali-treated alpha-MSH or [Nle4]-alpha-MSH. [Nle4, D-Phe7]-alpha-MSH was resistant to enzymatic degradation by serum enzymes. In addition, this peptide exhibited dramatically increased biological activity as determined by frog skin bioassay, activation of mouse melanoma adenylate cyclase, and stimulation of mouse melanoma cell tyrosinase activity. This Nle4, D-Phe7 synthetic analogue of alpha-MSH is a very porent melanotropin, 26 times as potent as alpha-MSH in the adenylate cyclase assay. The resistance of the peptide to enzymatic degradation and its extraordinarily potent and prolonged biological activity should make this analogue of alpha-MSH an important molecular probe for studying the melanotropin receptors of both normal and abnormal (melanoma) melanocytes.