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

[ Vol. 3 , Issue. 6 ]

Author(s):

Kimitaka Shiotani, Anna Miyazaki, Tingyou Li, Yuko Tsuda, Toshio Yokoi, Akihiro Ambo, Yusuke Sasaki, Sharon D. Bryant, Yunden Jinsmaa, Lawrence H. Lazarus and Yoshio Okada   Pages 583 - 598 ( 16 )

Abstract:


Opioidmimetics containing 3-[H-Dmt-NH-(CH2)m]-6-[H-Dmt-NH-(CH2)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 μ-affinity (Kiμ = 0.021 - 2.94 nM), δ-affinity (Kiδ = 1.06 - 152.6 nM), and μ selectivity (Kiδ/Kiμ = 14 - 3,126). The opioidmimetics (1 - 16) exhibited μ agonism in proportion to their μ-receptor affinity. δ- Agonism was essentially lacking in the compounds except (4) and (16), and (1) and (2) indicated weak δ antagonism (pA2 = 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 μ-opioid receptor ligands.

Keywords:

Opioidmimetic, 2',6'-dimethyl-L-tyrosin (Dmt), pyrazinone platform, Dmt-dimerization, opioid receptor affinity, '-agonism, δ-antagonism, structure-activity relationship

Affiliation:

Graduate School of Food and Medicinal Sciences, Kobe Gakuin University, Kobe 651-2180, Japan.



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