Further studies on the effect of lysine at the C-terminus of the Dmt-Tic opioid pharmacophore

Abstract

A wide range of bioactivities are induced by Lys when introduced at the C-terminus of the δ-opioid Dmt-Tic pharmacophore through the α-amine group, such as improved δ-antagonism, and presence of μ-agonism and μ-antagonism. We report the synthesis of a new series of compounds with the general formula H-Dmt-Tic-NH-(CH 2 ) 4 -CH(R)-R' (R = -NH 2 , -NH-Ac, -NH-Z; R' = CO-NH-Ph, -CO-NH-CH 2 -Ph, -Bid) in which Lys is linked to Dmt-Tic through its amine group side chain. The compounds (1-9) displayed a potent and selective δ-antagonism (pA 2 = 7.81-8.27) independent of the functionalized α-amine and carboxylic groups of the C-terminal Lys. This suggests direct application as a prototype intermediate, such as Boc-Dmt-Tic-ε-Lys(Z)-OMe, which could be applied in the synthesis (after Z or methyl ester removal) of unique "designed multiple ligands" containing the pharmacophore of the quintessential δ-antagonist Dmt-Tic and another opioid or biologically active non-opioid ligand.

Inhibition of the development of morphine tolerance by a potent dual μ-/δ-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph

“…The bioactivity of 3 , which exhibits antagonism toward both μ- and δ-opioid receptors in vitro, revealed the critical importance of a free amino group in Lys for the appearance of antagonism (Balboni, et al, 2006; Balboni, et al, 2007) and is supported by the in vivo studies herein. Since 3 was active following both subcutaneous and oral administrations, the data indicate transit through the gastrointestinal epithelial and blood-brain barriers.…”

Synthesis of a Potent and Selective 18F-Labeled δ-Opioid Receptor Antagonist Derived from the Dmt-Tic Pharmacophore for Positron Emission Tomography Imaging

“…Compounds 1 [H-Dmt-Tic-ϵ-Lys(Z)-OH] and 2 [H-Dmt-Tic-Phe-Lys(Z)-OH] were prepared stepwise by solution peptide synthetic methods, outlined in Schemes and , respectively. Boc-Tic-ϵ-Lys(Z)-OMe ( 3 ) was deprotected at its N-terminus by TFA treatment and condensed with Boc-Dmt-OH via WSC/HOBt. The resulting fully protected intermediate Boc-Dmt-Tic-ϵ-Lys(Z)-OMe ( 5 ) was Z deprotected by catalytic hydrogenation (H 2 , 10% Pd/C) and condensed with 4-fluorobenzoic acid via WSC/HOBt.…”

“…Receptor binding and functional bioactivities are reported in Table . Like the majority of the compounds of general formula H-Dmt-Tic-ϵ-Lys(R)-R′ (R = −NH 2 , −NH−Ac, −NH−Z; R′ = −CONH−Ph, CONH−CH 2 −Ph, −Bid [Bid, 1 H-benzimidazole-2-yl]), 1 exhibited subnanomolar affinity for δ-opioid receptors ( K i δ = 0.17 nM). As expected, the presence of a free carboxylic function in compounds containing the Dmt-Tic pharmacophore increases δ selectivity ( K i μ / K i δ = 240) by suppressing μ-opioid receptor affinity ( K i μ = 41.2 nM).…”

“…Chem . 1985 , 260 , 14–42), this paper uses the following additional symbols and abbreviations: AcOEt, ethyl acetate; AcOH, acetic acid; Bid, 1 H -benzimidazole-2-yl; Boc, tert- butyloxycarbonyl; DAMGO, [ d -Ala 2 , N -Me-Phe 4 ,Gly-ol 5 ]enkephalin; DEL C, deltorphin II (H-Tyr- d -Ala-Phe-Asp-Val-Val-Gly-NH 2 ); DMF, N,N -dimethylformamide; DMSO- d 6 , hexadeuteriodimethyl sulfoxide; Dmt, 2′,6′-dimethyl- l -tyrosine; DPDPE, ( d -Pen 2 , d -Pen 5 )-enkephalin; Et 2 O, diethyl ether; GPI, guinea pig ileum; HOBt, 1-hydroxybenzotriazole; HPLC, high-performance liquid chromatography; MALDI-TOF, matrix assisted laser desorption ionization time-of-flight; MVD, mouse vas deferens; NMM, 4-methylmorpholine; p A 2 , negative log of the molar concentration required to double the agonist concentration to achieve the original response; Pe, petroleum ether; TEA triethylamine; TFA, trifluoroacetic acid; Tic, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; TLC, thin-layer chromatography; WSC, 1-ethyl-3-[3′-dimethyl)aminopropyl]carbodiimide hydrochloride; Z, benzyloxycarbonyl. as a δ-opioid pharmacophore, ,,– we selected two δ-opioid reference compounds, H-Dmt-Tic-ϵ-Lys(Z)-OH and H-Dmt-Tic-Phe-Lys(Z)-OH, as potential tools for PET imaging on the basis of the similarity between the Z protecting group and the 4-fluorobenzoyl substituent.…”

Applications and Modifications of 1,2,3,4-Tetrahydroisoquinoline-3-Carboxylic Acid (Tic) in Peptides and Peptidomimetics Design and Discovery

“…Moreover, utilization of several kinds of protected or unprotected amino acids as the linker between the Dmt-Tic pharmacophore and the third aromatic nucleus yielded compounds endowed with distinct pharmacological activities [15][16][17]. The general structure of these analogues could be summarized as Dmt-Tic-Xaa-R (Xaa=amino acids, R= -Bid, -CH 2 Ph, -Ph)…”