Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the μ-opioid receptor and I2–imidazoline binding sites

Dardonville, Christophe; Fernandez-Fernandez, Cristina; Gibbons, Sarah-Louise; Ryan, Gary J.; Jagerovic, Nadine; Gabilondo, Ane M.; Meana, J. Javier; Callado, Luís F.

doi:10.1016/j.bmc.2006.06.007

Cited by 42 publications

(48 citation statements)

References 18 publications

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“…17,18 The second pharmacophore, required to complete the potential "designed multiple ligands," could be opioid compounds or other pharmacophores endowed with activity toward receptors exhibiting completely different (non-opioid) bioactivities. 16,19 More importantly, the second pharmacophore can be conveniently inserted using the deprotected α amino or carboxylic function depending on the required final bioactive product. In fact, very similar compounds were obtained when using fluorescent chromophores in place of the second pharmacophore.…”

Section: Discussionmentioning

confidence: 99%

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

Balboni

Congiu

Zotti

et al. 2007

Bioorganic & Medicinal Chemistry

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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.

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Section: Discussionmentioning

confidence: 99%

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

Balboni

Congiu

Zotti

et al. 2007

Bioorganic & Medicinal Chemistry

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“…All of the compounds were synthesized by following the procedures previously reported by us (18)(19)(20) (Fig. 2) and were tested against the clinically relevant stages of four different parasites: T. b. rhodesiense trypomastigotes, T. cruzi amastigotes, L. donovani amastigotes, and P. falciparum erythrocytic stages.…”

Section: Methodsmentioning

confidence: 99%

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Dardonville

Fernandez-Fernandez

Gibbons

et al. 2009

Antimicrob Agents Chemother

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A series of 44 4-aminopiperidine derivatives was screened in vitro against four protozoan parasites (Trypanosoma brucei rhodesiense, Trypanosoma cruzi, Leishmania donovani, and Plasmodium falciparum). This screening identified 29 molecules selectively active against bloodstream-form T. b. rhodesiense trypomastigotes, with 50% inhibitory concentrations (IC 50 ) ranging from 0.12 to 10 M, and 33 compounds active against the chloroquine-and pyrimethamine-resistant K1 strain of P. falciparum (IC 50 range, 0.17 to 5 M). In addition, seven compounds displayed activity against intracellular T. cruzi amastigotes in the same range as the reference drug benznidazole (IC 50 , 1.97 M) but were also cytotoxic to L-6 cells, showing little selectivity for T. cruzi. None of the molecules tested showed interesting antileishmanial activity against axenic amastigotes of L. donovani. To our knowledge, this is the first report of the antitrypanosomal activity of molecules bearing the 4-aminopiperidine skeleton.Tropical diseases due to parasitic protozoa cause great mortality and disability in the less developed world. Malaria and kinetoplastid diseases such as human African trypanosomiasis (HAT, or sleeping sickness), Chagas' disease, and leishmaniases are among the main neglected parasitic diseases, affecting hundreds of millions of people worldwide (http://www.dndi.org /index.php/diseases.html?idsϭ2). However, the low income of the affected populations does not make it financially attractive for pharmaceutical companies to invest in the development of new drugs against these diseases. The number of antiprotozoal drugs available is limited, and they are old, toxic, and losing efficacy due to the emergence of resistant parasites. New drugs are thus urgently needed (37).The landscape of drug discovery and development for new antiparasitic drugs has changed in the past few years thanks to financial backing from not-for-profit organizations and the involvement of public-private partnerships. The collaboration of various pharmaceutical companies with the Special Programme for Research and Training in Tropical Diseases (TDR), giving access to their compound libraries to help scientists search for new antiparasitic drugs, is a good example of the pragmatic approach required for the development of new medicaments for those neglected diseases (15,32,40). The screening of compound libraries to discover new hit and lead compounds against protozoan parasites has been used very efficiently by our group for the past few years. Very potent antiprotozoal compounds, active in vitro and in vivo against Trypanosoma brucei rhodesiense and Plasmodium falciparum, were identified by our group (16,17,38). These lead compounds were discovered by screening against T. brucei and P. falciparum a small library (Ͻ100 molecules) of dicationic compounds structurally related to known antiparasitic drugs (e.g., pentamidine, diminazene) but primarily synthesized by us for different medicinal targets.Following this successful approach, we have now selected from our i...

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“…According Dardonville et al [18], a 0.5 M solution of Boc 2 O (1 eq.) in CHCl 3 was added drop wise over a 2 h period to a 0.25 M solution of 1,3-diaminopropane (5 eq.)…”

Section: Tert-butyl 3-aminopropylcarbamatementioning

confidence: 99%

Grafting of aminated oligogalacturonans onto Douglas fir barks. A new route for the enhancement of their lead (II) binding capacities

Astier

Chaleix

Faugeron

et al. 2010

Journal of Hazardous Materials

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Synthesis and pharmacological studies of new hybrid derivatives of fentanyl active at the μ-opioid receptor and I2–imidazoline binding sites

Cited by 42 publications

References 18 publications

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

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

Antiprotozoal Activity of 1-Phenethyl-4-Aminopiperidine Derivatives

Grafting of aminated oligogalacturonans onto Douglas fir barks. A new route for the enhancement of their lead (II) binding capacities

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