The ä opioid antagonist H-Dmt-Tic-OH (2¢,6¢-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid) exhibits extraordinary ä receptor binding characteristics [Ki ä ) 0.022 nM; Ki í/Ki ä ) 150 000] and ä antagonism (pA2 ) 8.2; Ke ) 5.7 nM). A change in chirality of Dmt at CR (1, 2, 6, 8, 10, 13) curtailed ä receptor parameters, while replacement of its R-amino function by a methyl group (3) led to inactivity; Tyr-Tic analogues 4 and 11 weakly interacted with ä receptors. N-Alkylation of H-Dmt-Tic-OH and H-Dmt-Tic-Ala-OH with methyl groups produced potent ä-opioid ligands with high ä receptor binding capabilities and enhanced ä antagonism: (i) N-Me-Dmt-Tic-OH 5 had high ä opioid binding (Ki ä ) 0.2 nM), elevated ä antagonism on mouse vas deferens (MVD) (pA2 ) 8.5; Ke ) 2.8 nM), and nondetectable í activity with guinea pig ileum (GPI). (ii) N,N-Me2-Dmt-Tic-OH (12) was equally efficacious in ä receptor binding (Ki ä ) 0.12 nM; Ki í/Ki ä ) 20 000), but ä antagonism rose considerably (pA2 ) 9.4; Ke ) 0.28 nM) with weak í antagonism (pA2 ) 5.8; Ke ) 1.58 íM; GPI/MVD ) 1:5640). N-Me-(9) and N,N-Me2-Dmt-Tic-Ala-OH (15) also augmented ä opioid receptor binding, such that 15 demonstrated high affinity (Ki ä ) 0.0755 nM) and selectivity (Ki í/Ki ä ) 20 132) with exceptional antagonist activity on MVD (pA2 ) 9.6; Ke ) 0.22 nM) and weak antagonism on GPI (pA2 ) 5.8; Ke ) 1.58 íM; GPI/MVD ) 1:7180). Although the amidated dimethylated dipeptide analogue 14 had high Ki ä (0.31 nM) and excellent antagonist activity (pA2 ) 9.9; Ke ) 0.12 nM), the increased activity toward í receptors in the absence of a free acid function at the C-terminus revealed modest ä selectivity (Ki í/Ki ä ) 1 655) and somewhat comparable bioactivity (GPI/MVD ) 4500). Thus, the data demonstrate that N,N-(Me)2-Dmt-Tic-OH (12) and N,NMe2- Dmt-Tic-Ala-OH (15) retained high ä receptor affinities and ä selectivities and acquired enhanced potency in pharmacological bioassays on MVD greater than that of other peptide or non-peptide ä antagonists.
Evolution of the Dmt-Tic pharmacophore: N-terminal methylated derivatives with extraordinary δ opioid antagonist activity
SALVADORI, Severo;BALBONI, Gianfranco;GUERRINI, Remo;
1997
Abstract
The ä opioid antagonist H-Dmt-Tic-OH (2¢,6¢-dimethyl-L-tyrosyl-1,2,3,4-tetrahydroisoquinoline- 3-carboxylic acid) exhibits extraordinary ä receptor binding characteristics [Ki ä ) 0.022 nM; Ki í/Ki ä ) 150 000] and ä antagonism (pA2 ) 8.2; Ke ) 5.7 nM). A change in chirality of Dmt at CR (1, 2, 6, 8, 10, 13) curtailed ä receptor parameters, while replacement of its R-amino function by a methyl group (3) led to inactivity; Tyr-Tic analogues 4 and 11 weakly interacted with ä receptors. N-Alkylation of H-Dmt-Tic-OH and H-Dmt-Tic-Ala-OH with methyl groups produced potent ä-opioid ligands with high ä receptor binding capabilities and enhanced ä antagonism: (i) N-Me-Dmt-Tic-OH 5 had high ä opioid binding (Ki ä ) 0.2 nM), elevated ä antagonism on mouse vas deferens (MVD) (pA2 ) 8.5; Ke ) 2.8 nM), and nondetectable í activity with guinea pig ileum (GPI). (ii) N,N-Me2-Dmt-Tic-OH (12) was equally efficacious in ä receptor binding (Ki ä ) 0.12 nM; Ki í/Ki ä ) 20 000), but ä antagonism rose considerably (pA2 ) 9.4; Ke ) 0.28 nM) with weak í antagonism (pA2 ) 5.8; Ke ) 1.58 íM; GPI/MVD ) 1:5640). N-Me-(9) and N,N-Me2-Dmt-Tic-Ala-OH (15) also augmented ä opioid receptor binding, such that 15 demonstrated high affinity (Ki ä ) 0.0755 nM) and selectivity (Ki í/Ki ä ) 20 132) with exceptional antagonist activity on MVD (pA2 ) 9.6; Ke ) 0.22 nM) and weak antagonism on GPI (pA2 ) 5.8; Ke ) 1.58 íM; GPI/MVD ) 1:7180). Although the amidated dimethylated dipeptide analogue 14 had high Ki ä (0.31 nM) and excellent antagonist activity (pA2 ) 9.9; Ke ) 0.12 nM), the increased activity toward í receptors in the absence of a free acid function at the C-terminus revealed modest ä selectivity (Ki í/Ki ä ) 1 655) and somewhat comparable bioactivity (GPI/MVD ) 4500). Thus, the data demonstrate that N,N-(Me)2-Dmt-Tic-OH (12) and N,NMe2- Dmt-Tic-Ala-OH (15) retained high ä receptor affinities and ä selectivities and acquired enhanced potency in pharmacological bioassays on MVD greater than that of other peptide or non-peptide ä antagonists.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
