Cyclic lactam analogs of Ac-[Nle4].alpha.-MSH4-11-NH2

Abstract

Two side-chain cyclic lactam analogues of the 4-11 fragment of alpha-melanocyte-stimulating hormone (alpha-MSH), Ac-[Nle4,D-Orn5,Glu8]alpha-MSH4-11-NH2 and Ac-[Nle4,D-Orn5,D-Phe7,Glu8]alpha-MSH4-11-NH2, were prepared on p-methylbenzhydrylamine resin by using a combination of N alpha-Boc and N alpha-Fmoc synthetic strategies with diphenyl phosphorazidate mediated cyclization. The melanotropin activities of these two analogues were examined and compared relative to those of alpha-MSH, Ac-[Nle4]alpha-MSH4-11-NH2, and Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. In the frog (Rana pipiens) skin bioassay, the L-Phe7 17-membered ring cyclic analogue was slightly more potent than the linear Ac-[Nle4]alpha-MSH4-11-NH2 and exhibited prolonged melanotropic bioactivity (greater than or equal to 4 h). In this same assay, the D-Phe7 cyclic analogue was more than 100-fold less potent than the L-Phe cyclic analogue and was 10,000 times less potent than linear Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. In the lizard skin (Anolis carolinensis) bioassay, the L-Phe7 cyclic analogue was 100-fold less potent than Ac-[Nle4]alpha-MSH4-11-NH2, while the D-Phe7 cyclic analogue was 10,000-fold less potent than both Ac-[Nle4]alpha-MSH4-11-NH2 and the D-Phe7 linear derivative Ac-[Nle4,D-Phe7]alpha-MSH4-11-NH2. The solution conformation of these two cyclic analogues in dimethyl sulfoxide-d6 was examined by 1D and 2D 500-MHz 1H NMR spectroscopy. Our analysis suggests an H bond stabilized C10 (or C13) turn for the D-Phe7 cyclic structure while the L-Phe7 analogue is more conformationally flexible.(ABSTRACT TRUNCATED AT 250 WORDS)

Structure and dynamics of ?-MSH using DRISM integral equation theory and stochastic dynamics

“…The His 6 imidazole ring formed a roughly T-shaped alignment with the phenyl ring of Phe 7 . The details of this structure are in good agreement with the structure proposed by Hruby and co-workers on the basis of their nmr and structure-function studies, 37 though it has not been reported before in theoretical studies.…”

“…This kind of spatial arrangement was proposed to be important to the potency of the hormone 37 and was also observed in the structure determined in our previous study. 66 Another interesting question about the conformation of ␣-MSH is whether the biologically active structure is stabilized by a salt bridge.…”

“…[32][33][34][35] However, it has also been proposed that the positive charge on the Arg 8 side chain may not be very important for the function of the hormone. 36,37 The presence of blocking groups on the termini, especially the N-terminus, is very important for the potency of desacetyl-␣-MSH and its analogues. In particular, substitutions of the N-terminal acetyl group with larger or more lipophilic groups lead to large losses in potency 2,38,39 in some studies, though not in others.…”

Solution structures of cyclic melanocortin agonists and antagonists by NMR

“…22, 23 The results of energy calculations for ␣-MSH and the c[Cys 4 , Cys 10 ]␣-MSH showed that the Glu 5 and Arg 8 side chains are in close proximity and that a salt bridge between the two side chains may stabilize the biologically active conformation of ␣-MSH. 24,25 In a later study on ␣-MSH and its cyclic analogues, Nikiforovich et al 26 proposed a conformational model for binding and signal transduction, where the side chains of His 6 , L/D-Phe 7 , and Trp 9 residues form a continuous hydrophobic surface and the Arg 8 side chain is oriented away from them.…”

Systemic Delivery of Melanotan II through the Ocular Route in Rabbits

“…It can induce follicular melanogenesis in some rodents and dogs 11 and has been found to be physiologically stable and long acting in animals. 10,[12][13][14] As with most peptides, the oral bioavailability of melanotan II is low and the drug must be administered as a parenteral, which is impractical for chronic dosing. In order to better accommodate this problem, the systemic delivery of melanotan II through other routes of administration has been investigated.…”