Mikihiko Obayashi

Structure-activity relationships in the C-terminal part of luteinizing hormone releasing hormone (LH-RH)

Abstract Five new analogs of LH-RH(pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), ( Des-Gly-NH 2 10 , Pro-methylamide9)-LH-RH, ( Des-Gly-NH 2 10 , Pro-propylamide9)-LH-RH, ( Des-Gly-NH 2 10 , Pro-ethanolamide9)-LH-RH, ( Des-Gly-NH 2 10 , Pro-pyrrolidineamide9)-LH-RH and ( Des-Gly-NH 2 10 , Pro-morpholineamide9)-LH-RH were synthesized and evaluated for the hormonal activity. The activities of these new analogs were compared with those of LH-RH and our previously reported highly potent analog, ( Des-Gly-NH 2 10 , Pro-ethylamide9)-LH-RH. The results demonstrate a significant contribution of the total chain-length of the hormone for the hormonal action.

Syntheses and biological activities of analogs of luteinizing hormone releasing hormone (LH-RH)

Twenty analogs of luteinizing hormone releasing hormone (LH-RH or pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2), i.e., , , [Pro1]-, [Phe2]-, [3-Me-His2]-, [Lys2]-, [Arg2]-, [Ala4]-, [Thr4]-, [Gln5]-, [Cl-Tyr5]-, [di-Cl-Tyr7]-, [Gly7]-, [Ala7]-, [Val7] [Ile7]-, [Nle7]-, [Lys8]-, [Orn8]-, and [Ala10]-LH-RH, were synthesized by the fragment condensation method and some biological properties of these decapeptide amides were studied. On the basis of in,vitro and in,vivo biological activities of these analogs, structure-activity relationships were discussed.

An improved synthesis of thyrotropin releasing hormone (TRH) and crystallization of the tartrate

An improved synthesis of thyrotropin releasing hormone (TRH), pGlu-His-Pro-NH2, is reported. Z-pGlu-ONB (N-hydroxy-5-norbornene-2,3-dicarboximide ester) was reacted with H-His-OH to yield a crystalline Z-pGlu-His-OH which was coupled with H-Pro-NH2 by the HONBDCC method to give Z-pGlu-His-Pro-NH2 as a fine crystal. Hydrogenation of this protected tripeptide yielded pure TRH nearly quantitatively. The optical purity of TRH thus obtained was confirmed by the method L- and D- amino acid oxidase digestion. The crystallization of TRH was achieved as a tartrate, and the properties of the crystalline TRH-tartrate are described.

Synthesis and reduction of 11β,17α-dihydroxy-21-methylpregna-1,4-diene-3,20,21-trione 17-acylates

Abstract 11β,17α-Dihydroxy-21-methylpregna-1,4-diene-3,20,21-trione 17-acylates [propionate (IVb), n-butyrate (IVc) and benzoate (IVd)] were synthesized from prednisolone by a sequence of reactions, which involved 21-hydroxymethylation, acylation and rearrangement with alumina. Similarly, 9α-fluoro, 6α-methyl and 9α-fluoro-16α-methyl derivatives (IVe-h) were synthesized starting with 9α-fluoroprednisolone, 6α-methylprednisolone and dexamethasone, respectively. Microbiological reduction of these 17-acyloxy-20,21-diketosterodis (IV) with yeast or Streptomyces species afforded 11β,17α,21αF-trihydroxy-21-methylpregna-1,4-diene-3,20-dione (V), the 17-acylates (VI) and the 21-acylates (VII). On the other hand, sodium borohydride reduction of IV afforded the epimeric 21βF-hydroxy compounds, 11β,17α,21βF-trihydroxy-21-methylpregna-1,4-diene-3,20-dione 17-acylates (VIII) and 21-acylates (IX).