Susumu Shinagawa

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.

Synthetic analogs of luteinizing hormone releasing hormone (LH-RH) substituted in position 6 and 10.

Abstract A series of peptide analogs of luteinizing hormone releasing hormone (LH-RH), altered at position 6 and 10, was synthesized and evaluated in vivo for the ability to induce ovulation in the diestrous rat and in vitro for ability to release pituitary luteinizing hormone and follicle stimulating hormone. All the analogs with D-amino acid substitutions at position 6, even those with large bulky side chain, exhibited an amazingly high potency compared with the parent hormone, LH-RH. On the basis of the biological activities, structure-activity relationships in the central part of this molecule were discussed in detail.

Some analogs of luteinizing hormone releasing hormone (LH-RH) having intense ovulation-inducing activity

Five new analogs of luteinizing hormone releasing hormone (LH-RH), des-Gly10-[Ala6]-LH-RH-ethylamide, des-Gly10-[D-Ala6]-LH-RH-ethylamide, des-Gly10-[α-aminoisobutyric acid6]-LH-RH-ethylamide, des-Gly10-[Phe5, D-Ala6]-LH-RH-ethylamide and des-Gly10-[Ile5, D-Ala6]-LH-RH-ethylamide were synthesized and evaluated for the ovulation-inducing activity in the rat, and it was found that the analogs, des-Gly10-[D-Ala6]-LH-RH-ethylamide and des-Gly10-[Phe5, D-Ala6]-LH-RH-ethylamide, were 50 times or more active than the original molecule.

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.

Emeriamine, an antidiabetic β-aminobetaine derived from a novel fungal metabolite

Abstract Emeriamine [(R)-3-amino-4-trimethylaminobutyric acid], derived from a novel fungal metabolite “emericedin” [(R)-3-acetylamino-4-trimethylaminobutyric acid], was proved to be a strong and specific inhibitor of carnitine-dependent oxidation of long chain fatty acid (IC 50 ; 3.2 × 10 −6 M) and its main inhibition site was shown to be carnitine palmitoyltransferase I located on the outer-surface of the mitochondrial inner membrane. Emeriamine also showed hypoglycemic and antiketogenic activities in a dose-dependent manner (1–10 mg/kg) when administered orally to fasted normal and diabetic animals.

Stereo-chemical studies on the sulfoxide of 5,6-cis-carbapenem antibiotics, C-19393 components

Abstract The absolute configuration at the sulfoxide of 5,6- cis -carbapenem antibiotics is discussed on the basis of chemical reactions and the CD spectral data. Some stereoisomers at the side chain were synthesized from C-19393 H 2 by the combination of hydrogenation, oxidation and Z,E -isomerization. The CD spectral studies revealed that the Cotton effects of stereoisomers at the sulfoxide indicated clear opposite signs at both 260–275 and 280–300 nm regions. Further CD spectral studies on the derivatives elucidated that these Cotton effects may reflect two chromophores; for the former region and for the latter. In conclusion, these naturally occurring 5,6- cis -carbapenem antibiotics have been shown to possess the R -configuration at the sulfoxide.

Correlation between pharmacological and opiate receptor binding activities of tetrapeptide acylhydrazide analogs of enkephalin.

The pharmacological and opiate receptor binding activities of four synthetic tetrapeptide acylhydrazide analogs of enkephalin (EK compound) were compared with those of reference compounds. EK-159 administered subcutaneously was less analgesic, while EK-209, EK-259 and EK-272 were more potent than morphine in the hot plate, Haffners and phenylquinone writhing tests in mice. EK-272 being the most active was comparable to what was found with FK-33824. IC50 values of EK compounds in a sodium-free medium in the opiate receptor binding assay were lower than the values seen with morphine. The binding activities of EK compounds in 100 mM NaCl medium showed a clearer correlation with their analgesic activities than was seen in the absence of sodium ion. The binding affinity of EK-272 was the highest and the sodium response ratio (IC50 + NaCl/IC50-NaCl) was slightly lower than that of pentazocine. The analgesic action in rodents, respiratory inhibition in rabbits, inhibition of intestinal movement in mice, and hyperthermic action in rats, were all qualitatively, but not quantitatively similar to the effects seen with morphine. The analgesic action of EK compounds was relatively resistant to the antagonizing effect of naloxone and the EK compounds modified the analgesic action of morphine. These properties were inversely correlated with the sodium response ratios.

Role of methionine in the facilitated cleavage of aromatic ethers by methanesulphonic acid

Aromatic ethers, such as anisole or phenetole, were cleaved smoothly with methanesulphonic acid in the presence of methionine, which acted as an alkyl acceptor to form methionine S-methyl (or ethyl)sulphonium salt.