1. Nucleoside peptides. 10. Synthesis and T-cell immunostimulatory properties of certain peptide derivatives of 6-azacadeguomycin
W B Jolley, B S Sharma, R K Robins, G R Revankar, K Ramasamy J Med Chem . 1989 Aug;32(8):1905-9. doi: 10.1021/jm00128a036.
Several amino acid and peptide conjugates of 6-azacadeguomycin (6-amino-1-beta-D-ribofuranosyl-4,5-dihydro-4-oxopyrazolo[3,4-d]py rimidine- 3-carboxylic acid, 2) have been prepared in good yields, via a two-step procedure involving 1-hydroxybenzotriazole and 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride mediated coupling of 2 with an appropriately protected amino acid or peptide, followed by ammonolysis. Thus, condensation of 2 with L-phenylalanine methyl ester, glycine ethyl ester, and L-glutamic acid diethyl ester gave the corresponding protected linear nucleoside peptides (3, 5 and 7, respectively). Subsequent ammonolysis of 3, 5 and 7 furnished L-phenylalanine amide (4), glycine amide (6) and L-glutamic acid diamide (8) conjugates of 6-azacadeguomycin, respectively. Saponification of 7 gave the corresponding L-glutamic acid derivative 9. A similar coupling of 2 with L-phenylalaninyl-N epsilon-nitro-L-arginine methyl ester trifluoroacetate and subsequent ammonolysis (after catalytic hydrogenation) gave L-phenylalaninyl-L-arginine amide conjugate (12) of 6-azacadeguomycin. Compounds 2, 4, 6, 8, 9, and 12 were evaluated for their ability to potentiate T-cell responses to plant mitogens, in comparison with cadeguomycin (1). Compounds 4, 6, and 9 exhibited an increase in the T-cell proliferation in a dose-dependent manner.
2. Endothelin-1 and endothelin-3 modulate dopaminergic neurons through different mechanisms
H Yokogoshi, K Horie, A Morita Life Sci . 1995;57(8):735-41. doi: 10.1016/0024-3205(95)02002-z.
Novel vasoconstrictor peptides, endothelin-1 (ET-1) and endothelin-3 (ET-3), are also known as neuropeptides or neuromodulators. When either ET-1 or ET-3 was administered to the rat striatum via a microinjection needle, the dopamine release from the striatum dose-dependently increased. Pretreatment with a glutamate receptor blocker, glutamate diethyl ester hydrochloride, inhibited the dopamine release induced by ET-3, whereas it further enhanced the dopamine release by ET-1. This suggests that ET-1 directly induces the dopamine release, whereas the action of ET-3 is mediated by glutamate receptors. We postulate that this difference may result from the different distributions of endothelin receptors: ETA receptors may be present on the dopaminergic neurons, but ETB receptors on the glutamatergic neurons.
3. Excitation of rat striatal large neurons by dopamine and/or glutamate released from nerve terminals via presynaptic nicotinic receptor (A4beta2 type) stimulation
H Amano, T Amano, H Matsubayashi, M Sasa Jpn J Pharmacol . 2001 Aug;86(4):429-36. doi: 10.1254/jjp.86.429.
Previous in vivo experiments using rats anesthetized with chloral hydrate have revealed that nicotine applied iontophoretically increased firing of striatal neurons receiving excitatory dopaminergic input from the substantia nigra, and nicotine-induced firing was inhibited by domperidone, a dopamine D2 antagonist. The results suggest that nicotine increases release of dopamine from the terminals of dopaminergic neurons. Therefore, we performed the present patch clamp study using slice and acutely dissociated preparations of the rat striatum to elucidate the mechanisms underlying the nicotine-induced excitation of striatal neurons. Application of nicotine (100 microM) to large striatal neurons in slice preparations did not produce any effect on the resting membrane potential, but did increase the frequency of miniature postsynaptic potentials (mpps) and action potentials in all 15 neurons tested. The nicotine-induced increase in mpps and action potentials were inhibited during simultaneous application of domperidone; L-glutamic acid diethyl ester hydrochloride, a non-selective glutamate receptor antagonist; and/or dihydro-beta-erythroidine, a central nicotinic acetylcholine receptor (alpha4beta2 type) antagonist. Postsynaptic current was not induced by nicotine applied by U-tube in 96% of acutely dissociated striatal neurons. The present findings suggest that nicotine mainly acts on the presynaptic nicotinic receptors in the nerve terminals to release neurotransmitters such as dopamine and/or glutamate, thereby activating the striatal large neurons.
