Because polypeptides present a repeating sequence of amide bonds, lactams provide good model compounds for investigating the angular dependencies of coupling constants over a range of rigid conformations. A number of ¹³C labeled lactams were synthesized to cover a range of dihedral angles; experimental and theoretical carbon-carbon and carbon-hydrogen coupling constants were obtained to give the relationships between the vicinal coupling constants ³J[C(O)-N-C-C], ³J[C(O)-N-C-H] and dihedral angle φ. Vicinal ¹³C-¹³C coupling constants for dihedral angles in the range of 90° to 180° were obtained unambiguously from the coupling between the carbonyl and carbons in the side chains of lactams. However, due to coupling via multiple paths, vicinal ¹³C-¹³C coupling constants for dihedral angles ranging from 0° to 90° were estimated by excluding the contributions from the geminal ²J[C(O)-C-C] or vicinal ³J[C(O)-C-C-C] couplings in the lactam rings. The experimental and theoretical results show that the angular dependence of vicinal ¹³C-¹³C coupling constants do not follow a simple Karplus type relationship, especially at small dihedral angles. It was found that geminal ²J[C(O)-N-C] were small ( < 0.3 Hz). However, the ²J[C(O)-N-C] in the cis arrangement are shifted to about 2.2 Hz in N-methyl substituted lactams while in the trans arrangement the values are about 4.4 Hz. Geminal ¹³C-¹³C coupling constants ²J[(C(O)-N-C)] also provide a useful tool in stereochemical studies.

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Chemistry / Doctoral / Doctor of Philosophy

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A number of α-melanotropin analogues have been prepared. Insight towards the development and understanding of the functional roles of each of the amino acid residues important for high melanotropic potency in a number of biological systems was studied. The melanotropin analogue Ac- α-MSH₄₋₁₂-NH₂ contains all of the structural requirements necessary for obtaining full biological potency on the lizard (Anolis carolinensis) melanophore and S-91 mouse melanoma. On the frog (Rana pipiens) melanophore, the melanotropin analogue Ac-[Nle⁴]-α-MSH₄₋₁₃-NH₂ possesses full melanotropic potency relative to the native hormone. The smallest melanotropin analogue capable of eliciting any biological response was Ac-α-MSH₆₋₉-NH₂ (Ac-His-Phe-Arg-Trp-NH₂) on all biological systems studied. The low biological activity found in previous studies for smaller melanotropin analogues may have been due to a trace contamination of a potent melanotropin. The importance of each of the thirteen amino acid residues of α-melanotropin in contributing to the melanotropic actions in a number of biological systems is discussed. We were unable to confirm the reported presence of a second independent active sequence in α-melanotropin. The structural requirements for prolongation of biological activity (following removal of exogenous hormone from the assay medium) and enzyme stability have been studied. Analysis suggests species-dependent differences in the structural relationships of the amino acid residues in the 4, 7 and 11 positions for prolonged melanotropic response. Analogues prepared with D-phenylalanine in place of its L-enantiomer in the seventh positions of α-melanotropin analogues generally results in an increased resistance to enzymatic degradation towards rat brain homogenate, rat serum, and to the purified enzymes, trypsin and chymotrypsin. Some of these analogues have been shown to be useful probes for the understanding of melanotropic actions in a number of biological systems. Two α-melanotropin analogues have been prepared which possess partial agonism on the mouse melanoma adenylate cyclase assay. A number of these analogues should prove useful in future studies directed towards a more detailed study of melanotropin receptor systems in a large variety of biological systems. The first known synthesis of melanin concentrating hormone (MCH) is reported. The overall synthetic yield of this cyclic heptadecapeptide was 14%. The chemical, physical and biological properties of synthetic MCH and naturally occurring telost MCH were in agreement. MCH was found to be a full agonist in stimulating melanosome dispersion in both the frog and lizard bioassay. Therefore MCH can stimulate melanosome dispersion or contraction depending upon the bioassay studied. Preliminary studies were done towards understanding the mechanisms of MCH action on telost fish.

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