Design, synthesis and nootropic activity of new analogues of sunifiram and sapunifiram, two potent cognition-enhancers

Martini, Elisabetta; Salvicchi, Alberto; Ghelardini, Carla; Manetti, Dina; Dei, Silvia; Guandalini, Luca; Martelli, Cecilia; Melchiorre, Michele; Cellai, Cristina; Scapecchi, Serena; Teodori, Elisabetta; Romanelli, Maria Novella

doi:10.1016/j.bmc.2009.08.055

Cited by 10 publications

(4 citation statements)

References 22 publications

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“…Playing the same game of scaffold hopping, we shifted to a 1,4-diaminobenzene scaffold obtaining some very interesting compounds like 21 (MED value ¼ 0.01 mg/kg) 14 . Also in the case of Sunifiram, we tried to change the size of the cycle 15 : while reduction of the size-impaired nootropic activity (22, MED value ¼ 1.0 mg/kg), its enlargement maintains a good activity (23, MED value ¼ 0.1 mg/kg). Finally changing the relative position of the nitrogen atoms of piperazine was definitely detrimental for activity (24, MED value ¼ 1.0 mg/kg).…”

Section: Medicinal Chemistrymentioning

confidence: 99%

“…Summarizing the results reported in our papers, where the interested scientists are addressed for details in methods and procedures [5][6][7][8]10,[12][13][14][15][16][17][18] , the following were the main findings: (1) Unifiram and Sunifiram antagonized memory disruption is produced not only by the muscarinic antagonist scopolamine but also by mecamylamine (nicotinic antagonist), baclofen (GABA agonist), clonidine (alpha-2 agonist), and NBQX (AMPA antagonist) 16,18 . The MEDs varied according to the amnestic drug and administration way.…”

Section: Pharmacologymentioning

confidence: 99%

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Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings

Gualtieri

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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This paper is a review of the work of my former academic group of research in the past 15 years, in the field of cognition enhancers (also called nootropics) that identified two very potent molecules: Unifiram and Sunifiram that for a variety of reasons were not protected by a patent. Some 12 years after their disclosure (2000) I casually found that on the web, there were dozens of sites offering Unifiram and Sunifiram as drugs that improve cognition in healthy individuals even if only few preclinical studies were done and their long-term toxicity was unknown.

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Section: Medicinal Chemistrymentioning

confidence: 99%

Section: Pharmacologymentioning

confidence: 99%

Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings

Gualtieri

2015

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…In addition, the amide group (CONH 2 ) has an important place in medicinal chemistry as an efficient pharmacophore and constitutes an integral part in many synthetic and natural active compounds [20][21][22][23]. These derivatives have shown interesting therapeutic properties such as: anticonvulsant [24], antitubercular [25], antimicrobial [26], analgesic and anti-inflammatory [27], insecticide [28], anticancer [29], fibrinolytic [30], nootropic [31], and antihypertensive [32] (Fig. 2).…”

Section: Introductionmentioning

confidence: 99%

New efficient synthesis, spectroscopic characterization, and X-ray analysis of novel β-enaminocarboxamide derivatives

et al. 2023

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A new series of β-enaminocarboxamide was synthesized via the addition of chlorosulfonyl isocyanate to β-enaminones. The prepared intermediates were converted to corresponding β-enaminocarboxamides by removal of the chlorosulfonyl group using methanol. The resulting compounds were obtained in excellent yields in the range of (80-92%) and were characterized by 1 H, 13 C, HMBC, HSQC NMR spectroscopy, and IR spectroscopy as well as elemental analysis. 1 H-NMR spectrum showed a non-equivalence of the primary amide protons which was due to H-bonding. β-enaminocarboxamide 5h was obtained as a crystal and was subjected to X-ray analysis. Results showed that 5h crystallizes in the monoclinic crystal system with C2/c space group and the ORTEP confirmed the presence of intramolecular H-bonds.

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“…Pyrrolidone derivatives called “nootropics” enhance learning and memory. Sunifiram (DM235) characterized by a 1,4‐diamino‐cyclohexane (Martini et al, ) shows cognitive‐enhancing properties with a potency of four orders of magnitude higher than piracetam (Manetti et al, ). In fact, nootropics stimulate cognitive processes through multiple signaling systems, in which activation of receptors, second messengers, and gene expression are involved (Amadio et al, ).…”

Section: Introductionmentioning

confidence: 99%

Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine‐binding site of N‐methyl‐D‐aspartate receptor

et al. 2013

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Sunifiram is a novel pyrrolidone nootropic drug structurally related to piracetam, which was developed for neurodegenerative disorder like Alzheimer's disease. Sunifiram is known to enhance cognitive function in some behavioral experiments such as Morris water maze task. To address question whether sunifiram affects N-methyl-D-aspartate receptor (NMDAR)-dependent synaptic function in the hippocampal CA1 region, we assessed the effects of sunifiram on NMDAR-dependent long-term potentiation (LTP) by electrophysiology and on phosphorylation of synaptic proteins by immunoblotting analysis. In mouse hippocampal slices, sunifiram at 10-100 nM significantly enhanced LTP in a bell-shaped dose-response relationship which peaked at 10 nM. The enhancement of LTP by sunifiram treatment was inhibited by 7-chloro-kynurenic acid (7-ClKN), an antagonist for glycine-binding site of NMDAR, but not by ifenprodil, an inhibitor for polyamine site of NMDAR. The enhancement of LTP by sunifilam was associated with an increase in phosphorylation of α-amino-3-hydroxy-5-methylisozazole-4-propionate receptor (AMPAR) through activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and an increase in phosphorylation of NMDAR through activation of protein kinase Cα (PKCα). Sunifiram treatments at 1-1000 nM increased the slope of field excitatory postsynaptic potentials (fEPSPs) in a dose-dependent manner. The enhancement was associated with an increase in phosphorylation of AMPAR receptor through activation of CaMKII. Interestingly, under the basal condition, sunifiram treatments increased PKCα (Ser-657) and Src family (Tyr-416) activities with the same bell-shaped dose-response curve as that of LTP peaking at 10 nM. The increase in phosphorylation of PKCα (Ser-657) and Src (Tyr-416) induced by sunifiram was inhibited by 7-ClKN treatment. The LTP enhancement by sunifiram was significantly inhibited by PP2, a Src family inhibitor. Finally, when pretreated with a high concentration of glycine (300 μM), sunifiram treatments failed to potentiate LTP in the CA1 region. Taken together, sunifiram stimulates the glycine-binding site of NMDAR with concomitant PKCα activation through Src kinase. Enhancement of PKCα activity triggers to potentiate hippocampal LTP through CaMKII activation.

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Design, synthesis and nootropic activity of new analogues of sunifiram and sapunifiram, two potent cognition-enhancers

Cited by 10 publications

References 22 publications

Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings

Unifi nootropics from the lab to the web: a story of academic (and industrial) shortcomings

New efficient synthesis, spectroscopic characterization, and X-ray analysis of novel β-enaminocarboxamide derivatives

Novel nootropic drug sunifiram enhances hippocampal synaptic efficacy via glycine‐binding site of N‐methyl‐D‐aspartate receptor

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