| Abstract
| - The δ opioid antagonist H-Dmt-Tic-OH(2‘,6‘-dimethyl-l-tyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) exhibits extraordinary δ receptor bindingcharacteristics [Kiδ = 0.022nM;Kiμ/Kiδ= 150 000] and δ antagonism (pA2 = 8.2;Ke = 5.7 nM). A change in chirality ofDmtat Cα (1, 2, 6, 8, 10, 13) curtailed δ receptorparameters, while replacement of its α-aminofunction by a methyl group (3) led to inactivity; Tyr-Ticanalogues 4 and 11 weakly interactedwith δ receptors. N-Alkylation of H-Dmt-Tic-OH andH-Dmt-Tic-Ala-OH with methyl groupsproduced potent δ-opioid ligands with high δ receptor bindingcapabilities and enhanced δantagonism: (i) N-Me-Dmt-Tic-OH 5 had high δopioid binding (Kiδ = 0.2 nM),elevated δantagonism on mouse vas deferens (MVD) (pA2 =8.5; Ke = 2.8 nM), and nondetectable μactivitywith guinea pig ileum (GPI). (ii)N,N-Me2-Dmt-Tic-OH (12)was equally efficacious in δ receptorbinding (Kiδ = 0.12 nM;Kiμ/Kiδ= 20 000), but δ antagonism rose considerably(pA2 = 9.4; Ke=0.28 nM) with weak μ antagonism (pA2 = 5.8;Ke = 1.58 μM; GPI/MVD = 1:5640).N-Me-(9)and N,N-Me2-Dmt-Tic-Ala-OH(15) also augmented δ opioid receptor binding, such that15demonstrated high affinity (Kiδ= 0.0755 nM) and selectivity(Kiμ/Kiδ= 20 132) with exceptionalantagonist activity on MVD (pA2 = 9.6;Ke = 0.22 nM) and weak antagonism on GPI(pA2 =5.8; Ke = 1.58 μM; GPI/MVD = 1:7180).Although the amidated dimethylated dipeptideanalogue 14 had highKiδ (0.31 nM) and excellentantagonist activity (pA2 = 9.9;Ke = 0.12nM), the increased activity toward μ receptors in the absence of afree acid function at theC-terminus revealed modest δ selectivity(Kiμ/Kiδ= 1 655) and somewhat comparable bioactivity(GPI/MVD = 4500). Thus, the data demonstrate thatN,N-(Me)2-Dmt-Tic-OH (12)and N,N-Me2-Dmt-Tic-Ala-OH (15) retained high δreceptor affinities and δ selectivities and acquiredenhanced potency in pharmacological bioassays on MVD greater than thatof other peptide ornon-peptide δ antagonists.
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