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-(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.