Synthesis of opioidmimetics, 3-[H-Dmt-NH(CH(2))(m)]-6-[H-Dmt-NH(CH(2))(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.
Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Kobe 651-2180, Japan.
Kimitaka
K
Shiotani
Anna
A
Miyazaki
Tingyou
T
Li
Yuko
Y
Tsuda
Toshio
T
Yokoi
Akihiro
A
Ambo
Yusuke
Y
Sasaki
Sharon D
SD
Bryant
Yunden
Y
Jinsmaa
Lawrence H
LH
Lazarus
Yoshio
Y
Okada
D000701:Analgesics, Opioid / Q000737:chemistry*; D006801:Humans; D018716:Molecular Mimicry; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D000701:Analgesics, Opioid; D011719:Pyrazines; D017450:Receptors, Opioid, mu