Kimitaka Shiotani

Potent in vivo antinociception and opioid receptor preference of the novel analogue [Dmt1]endomorphin-1.

[Dmt1]Endomorphin-1 is a novel analogue of the potent mu-opioid agonist endomorphin-1. Given the physiological role of endomorphin-1 in vivo, this compound was investigated to determine if the antinociception occurred through systemic, supraspinal or in a combination of both neuronal pathways. This compound exhibited a potent dose-dependent effect intracerebroventricularly in both spinal and supraspinal regions, and was blocked by opioid antagonist naloxone, which verified the involvement of opioid receptors. Specific opioid antagonists characterized the apparent receptor type: beta-funaltrexamine (mu1/mu2-irreversible antagonist) equally inhibited spinal- and central-mediated antinociception; on the other hand, naloxonazine (mu1-subtype) was ineffective in both neural pathways and naltrindole (delta-selective antagonist) partially (26%), though not significantly, blocked only the spinal-mediated antinociception. Therefore, spinal antinociception was primarily triggered by mu2-subtypes without involvement of mu1-opioid receptors; however, although a slight enhancement of antinociception by delta-receptors cannot be completely ruled out since functional bioactivity indicated mixed mu-agonism/delta-antagonism. In terms of the CNS action, [Dmt1]endomorphin-1 appears to act through mu2-opioid receptor subtypes.

Synthesis of Opioidmimetics, 3-[H-Dmt-NH(CH2)m]-6-[H-Dmt-NH(CH2)n]-2(1H)-pyrazinones, and Studies on Structure-Activity Relationships

Opioidmimetics containing 3-[H-Dmt-NH-(CH(2))(m)]-6-[H-Dmt-NH-(CH(2))(n)]-2(1H)-pyrazinone symmetric (m = n, 1-4) (1 - 4) and asymmetric (m, n = 1 - 4) aliphatic chains (5 - 16) were synthesized using dipeptidyl chloromethylketone intermediates. They had high mu-affinity (K(i)mu = 0.021 - 2.94 nM), delta-affinity (K(i)delta = 1.06 - 152.6 nM), and mu selectivity (K(i)delta/K(i)mu = 14 - 3,126). The opioidmimetics (1 - 16) exhibited mu agonism in proportion to their mu-receptor affinity. delta-Agonism was essentially lacking in the compounds except (4) and (16), and (1) and (2) indicated weak delta antagonism (pA(2) = 6.47 and 6.56, respectively). The data verify that a specific length of aliphatic linker is required between the Dmt pharmacophore and the pyrazinone ring to produce unique mu-opioid receptor ligands.

Immediate deamination from the aminomethyl group attached to 1,2-dihydropyrazin-2-one derivative during catalytic hydrogenation

Abstract The catalytic hydrogenation of 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one to remove benzyloxycarbonyl (Z) groups resulted in a side reaction. Purification by reverse-phase HPLC and analysis by proton nuclear magnetic resonance (1H NMR) spectroscopy identified the product as 3-aminomethyl-5,6-dimethyl-1,2-dihydropyrazin-2-one. It was determined through the synthesis of two 1,2-dihydropyrazin-2-one derivatives, composed of alanine and 2,3-diaminopropionic acid that deamination occurred specifically and easily (under atmospheric pressure and at the room temperature) only in the case of 6-benzyloxycarbonylaminomethyl-3,5-dimethyl-1,2-dihydropyrazin-2-one. The catalytic hydrogenation of 3,6-bis(benzyloxycarbonylaminomethyl)-5-methyl-1,2-dihydropyrazin-2-one specifically yields the deaminated product, 3-aminomethyl-5,6-dimethyl-1,2-dihydropyrazin-2-one.