Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

Salvadori, Severo; Fiorini, Stella; Trapella, Claudio; Porreca, Frank; Davis, Peg; Sasaki, Yoshiyuki; Ambo, Akihiro; Marczak, Ewa D.; Lazarus, Lawrence H.; Balboni, Gianfranco

doi:10.1016/j.bmc.2007.12.032

Cited by 11 publications

(11 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recently, a similar lack of correlation was observed by Hruby et al with 4-anilidopiperidine analogues 29. As expected and partially demonstrated for 3 ,24, 25 all N-methylated analogues of anilides and N 1 -Bid ( 5 , 8–11 ) revealed potent and selective δ-opioid antagonist activity (MVD, pA 2 = 8.06–9.90), confirming the importance of the hydrogen of –NH-Ph and N 1 H-Bid on the induction of δ agonism. Surprisingly, the substitution of Gly with L -Asp ( 6 ) or D -Asp ( 7 ) in reference compound 1 , gave two potent and quite selective δ antagonists (MVD, pA 2 = 9.40 and 8.62, respectively) despite of the presence of the –NH-Ph hydrogen.…”

Section: Resultssupporting

confidence: 76%

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

et al. 2008

Self Cite

View full text Add to dashboard Cite

Opioids containing the Dmt-Tic pharmacophore, especially the δ agonists H-Dmt-Tic-Gly-NH-Ph 1 and H-Dmt-Tic-NH-(S)CH(CH 2 -COOH)-Bid 4 (UFP-512) were evaluated for the influence of the substitution of Gly with aspartic acid, its chirality, and the importance of the -NH-Ph and N 1 H-Bid hydrogens relative to δ agonism. The results provide the following conclusions: (i) Asp increases δ selectivity by lowering μ affinity; (ii) -NH-Ph and N 1 H-Bid nitrogen methylation transforms δ agonists into δ antagonists; (iii) substitution of Gly with L-Asp/D-Asp in the δ agonist H-Dmt-TicGly-NH-Ph resulted in δ antagonists, while the same substitution in the δ agonist H-Dmt-Tic-NH-CH 2 -Bid yielded more selective δ agonists, H-Dmt-Tic-NH-(S)CH(CH 2 -COOH)-Bid and H-DmtTic-NH-(R)CH(CH 2 -COOH)-Bid; (iv) L-Asp seems important only for functional bioactivity, not receptor affinity; (v) H-Dmt-Tic-NH-(S)CH(CH 2 -COOH)-Bid(N 1 -Me) (10) revealed analgesia similar to 4, which was reversed by naltrindole only in the tail-flick test. Compounds 4 and 10 had opposite behaviours in mice: 4 caused agitation, while 10 gave sedation and convulsions.

show abstract

Section: Resultssupporting

confidence: 76%

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Adduct 4 was then refluxed with NH 4 OAc in toluene to give imidazole 5 with removal of water using a Dean–Stark apparatus. 7 Regioselective N -alkylation with ethyl 2-bromoacetate followed by a one-pot deprotection/cyclization sequence furnished the lactam core, which was reduced by borane to furnish amine 8 . The quaternary β-carbon did not pose a significant amount of steric hindrance for the HATU mediated amidation reaction with N -Boc-glycine.…”

Section: Chemistrymentioning

confidence: 99%

Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents

Nagle

Kuhen

et al. 2012

J. Med. Chem.

View full text Add to dashboard Cite

On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.

show abstract

“…To give more complexity, if possible, to the SAR related to the δ agonist containing the Dmt-Tic pharmacophore ( 1 , 4 ), here we complete the demonstration that all parts of the compounds can be altered resulting in different activities. For example: alkylation of 1 H -benzimidazol-2-yl (Bid) at N 1 yields only δ antagonists;19–21 substitution of Bid with other aromatic nuclei (benzoxazol-2-y; benzothiazol-2-yl; 1 H -indol-2-yl; 4-phenyl-1 H -imidazol-2-yl) generally furnish δ antagonists, but occasionally δ agonism can be maintained (1 H -imidazol-2-yl) 22. The portion -Gly*-Bid can be replaced by – Gly-NH-Ph or – Gly-NH-Bzl resulting in a dual μ agonist/ δ agonist or a μ agonist/ δ antagonist, respectively 13.…”

Section: Discussionmentioning

confidence: 99%

Role of 2′,6′-dimethyl-l-tyrosine (Dmt) in some opioid lead compounds

Balboni

Marzola

Sasaki

et al. 2010

Bioorganic & Medicinal Chemistry

Self Cite

View full text Add to dashboard Cite

Here we evaluated how the interchange of the amino acids 2′,6′-dimethyl-L-tyrosine (Dmt), 2′,6′-difluoro-L-tyrosine (Dft), and tyrosine in position 1 can affect the pharmacological characterization of some reference opioid peptides and pseudopeptides. Generally, Dft and Tyr provide analogues with a similar pharmacological profile, despite different pKa values. Dmt/Tyr(Dft) replacement gives activity changes depending on the reference opioid in which the modification was made. Whereas, H-Dmt-Tic-Asp*-Bid is a potent and selective δ agonist (MVD, IC50 = 0.12 nM); H-Dft-Tic-Asp*-Bid and H-Tyr-Tic-Asp*-Bid are potent and selective δ antagonists (pA2 = 8.95 and 8.85, respectively). When these amino acids are employed in the synthesis of deltorphin B and its Dmt1 and Dft1 analogues, the three compounds maintain a very similar δ agonism (MVD, IC50 0.32–0.53 nM) with a decrease in selectivity relative to the Dmt1 analogue. In the less selective H-Dmt-Tic-Gly*-Bid the replacement of Dmt with Dft and Tyr retains the δ agonism but with a decrease in potency. Antagonists containing the Dmt-Tic pharmacophore do not support the exchange of Dmt with Dft or Tyr.

show abstract

Role of benzimidazole (Bid) in the δ-opioid agonist pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502)☆

Cited by 11 publications

References 24 publications

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic

Imidazolopiperazines: Lead Optimization of the Second-Generation Antimalarial Agents

Role of 2′,6′-dimethyl-l-tyrosine (Dmt) in some opioid lead compounds

Contact Info

Product

Resources

About