ABSTRACTa-Melanocyte-stimulating hormone (a-MSH) reversibly darkens frog skins by stimulating melanosome movement (dispersion) within melanophores. Heat-alkali treatment of a-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) a-Melanotropin (a-MSH, a-melanocyte-stimulating hormone) is a tridecapeptide (Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-ArgTrp-Gly-Lys-Pro-Val-NH2) that is synthesized and secreted by the pars intermedia of the vertebrate pituitary (1). The amino acid residues that are important in the expression of melanotropic activity have been elucidated through systematic structure-function investigations of a-MSH and a-MSH fragments on amphibian melanophores (2, 3) and, to a lesser extent, on mammalian melanoma cells (4-6). Very little information is available, however, regarding the stereochemical and conformational correlates of biological activity in either of these two biological systems.Earlier reports have shown that heat-alkali treatment of crude or purified preparations of naturally occurring a-MSH produces a partially racemized product with altered activity on amphibian melanophores both in vivo and in vitro. Such changes in biological effects have been discussed in terms of "potentiation," "prolongation," and "retardation" (7-12). Although the precise biochemical mechanism by which these unusual biological properties were produced is unknown, it appeared possible that synthetic stereostructural tailoring of a-MSH might produce an analogue that would also possess these properties. Utilizing a high-resolution gas chromatographic method to localize and quantitate specific sites of racemization within the primary sequences of peptides, we obtained additional evidence which suggested that stereochemical substitution at position 7 (replacement of L-phenylalanine by D-phenylalanine) of a-MSH or [Nle4]-a-MSH would provide an analogue with the desired biological properties. Previous investigations have shown that [Nle4]-a-MSH is more potent than a-MSH on both amphibian melanophores (2, 6) and on stimulating melanoma adenylate cyclase (6, 13), and it is also resistant to inactivation by chloramine-T (14, 15), an oxidant used in peptide iodination. Because heat-alkali treatment of this analogue also resulted in "potentiation," "prolongation," and "retardation," it was clear that alteration of the methionine residue was not a requirement for the expression of these properties. Thus, it was decided to retain the benefits of the norleucine substitution in position 4 in the synthesis of the "definitive" peptide.We report here the synthesis of [Nle4, D-Phe7]-a-MSH and present data demonstrating its unique biological properties. These include prolonged biological activity, enhanced potency relative to a-MSH in a number of biological systems, and resistance to degradation by serum enzymes. The biological properties of this analogue provide...

A series of imidazo-fused heterocycles substituted with an aryloxy)alkylamine side chain were prepared as modifications to butoprozine (I) and found to possess calcium channel blocking activity similar in potency to that of bepridil in trachea smooth muscle and similar to that of verapamil in nitrendipine binding affinity in rabbit cardiac muscle. Of the various imidazo-fused heterocycles prepared, the imidazo[1,2-a]pyridines were also found to be potent local anesthetic agents. While most compounds in this series were equipotent to lidocaine in our initial screen, compounds 2 and 35 showed local anesthetic activity approximately 100 times more potent than lidocaine in our preliminary assays. These compounds represent a novel structural class of local anesthetic agents, and compound 2 is under further investigation.

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