Papers by Roberto de la Torre-Martinez
SummaryThe dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cor... more SummaryThe dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cortical regions and is involved in sensory and motor functions. In cortical regions, sensory responses are altered by motor activity, however, it is not known if such sensorimotor interactions also occur in the striatum and how they are modulated by dopamine (DA). To determine the impact of motor activity on striatal sensory processing, we performed in vivo whole-cell recordings in the DLS of awake mice during the presentation of tactile stimuli. Striatal medium spiny neurons (MSNs) were activated by both whisker stimulation and spontaneous whisking, however, responses to whisker deflection during ongoing whisking were attenuated. DA depletion reduced the representation of whisking in direct-pathway MSNs, but not in those of the indirect-pathway. Furthermore, DA depletion impaired the discrimination between ipsi- and contralateral sensory stimulation in both direct- and indirect- pathway M...
Nature Communications
The dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cortical r... more The dorsolateral striatum (DLS) receives excitatory inputs from both sensory and motor cortical regions. In the neocortex, sensory responses are affected by motor activity, however, it is not known whether such sensorimotor interactions occur in the striatum and how they are shaped by dopamine. To determine the impact of motor activity on striatal sensory processing, we performed in vivo whole-cell recordings in the DLS of awake mice during the presentation of tactile stimuli. Striatal medium spiny neurons (MSNs) were activated by both whisker stimulation and spontaneous whisking, however, their responses to whisker deflection during ongoing whisking were attenuated. Dopamine depletion reduced the representation of whisking in direct-pathway MSNs, but not in those of the indirect-pathway. Furthermore, dopamine depletion impaired the discrimination between ipsilateral and contralateral sensory stimulation in both direct and indirect pathway MSNs. Our results show that whisking affect...
ACS Chemical Neuroscience, 2019
Acetylcholine7 nicotinic receptors are widely expressed in the brain, where they are involved i... more Acetylcholine7 nicotinic receptors are widely expressed in the brain, where they are involved in the central processing of pain, as well as in neuropsychiatric, neurodegenerative and inflammatory processes. Positive allosteric modulators (PAM) show the advantage of allowing the selective regulation of different subtypes of acetylcholine receptors without directly interacting with the agonist binding site. Here we report the preparation and biological activity of a fluoro-containing compound, 1-(2',5'-dihydroxyphenyl)-3-(2-fluoro-4-hydroxyphenyl)-1-propanone (8, RGM079), that behaves as a potent PAM of the 7 receptors, and has a balanced pharmacokinetic profile and antioxidant properties comparable or even higher than well-known natural polyphenols. In addition, compound RGM079 shows neuroprotective properties in AD-toxicity related models. Thus, it causes a concentration-dependent neuroprotective effect against the toxicity induced by okadaic acid (OA) in the human neuroblastoma cell line SH-SY5Y. Similarly, in primary cultures of rat cortical neurons, RGM079 is able to restore the cellular viability after exposure to OA and amyloid peptide Aβ1-42, with cell death almost completely prevented at 10 and 30 M, respectively. Finally, compound RGM079 shows in vivo analgesic activity in the CFA-induced paw inflammation model, after intraperitoneal administration.
Effect of econazole and benzydamine on sensory neurons in culture
Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 2016
Econazole is an anti-mycotic agent widely used for the treatment of cutaneous fungal infections, ... more Econazole is an anti-mycotic agent widely used for the treatment of cutaneous fungal infections, and for the therapy of vaginal candidiasis. Topical application of this azole is generally safe, although some patients have complained of mild burning sensation/cutaneous irritation and itching, especially when administered intravaginally. The underlying mechanisms responsible of these adverse effects are poorly understood, though they suggest excitation of cutaneous nociceptor terminals. We report that exposure of primary cultures of rat nociceptors to econazole augments neuronal excitability. This effect appears mediated by increments in the intracellular Ca by stimulating Ca entry and release from the endoplasmic reticulum. Ca entry was not due to activation of thermo transient receptor potential (TRP) channels, suggesting a different ion channel targeted by the azole. Noteworthy, econazole-evoked responses were potentiated by a pro-inflammatory agent, which resulted in an increase i...
Future Medicinal Chemistry, 2016
Nicotine acethylcholine receptors (nAChRs) play critical roles in cognitive processes, neuroprote... more Nicotine acethylcholine receptors (nAChRs) play critical roles in cognitive processes, neuroprotection and inflammation. Results: According to their substituents, 1,3-diphenylpropan-1-one derivatives act as α7 nAChRs negative allosteric modulators (NAM, OMe) or Type I positive allosteric modulators (PAMs, OH). Compounds 7 and 31 were the most effective (989 and 666% enhancement of ACh-induced currents) and potent (EC50: 12.9 and 6.85 μM) PAMs. They exhibited strong radical scavenging values. Compound 31, selective over other neuronal nAChR subtypes and with acceptable pharmacokinetic profile, showed antinociceptive effects in a model of inflammatory pain. Conclusion: Compound 31 is a novel, potent and selective α7 nAChR PAM, displaying antioxidant and analgesic activities. The 1,3-diphenylpropan-1-one scaffold could be the base toward more advanced type I PAMs for the treatment of nAChR-mediated diseases.
Journal of medicinal chemistry, Jan 4, 2016
Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is curre... more Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and other diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl) ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl) ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC50 = 40±4 µM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentration-dependent inhibition of menthol-induced TRPM8 currents (IC50=367±24 nM). Molecular modelling studies using a homology model of a single rat TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, d...
RSC Advances, 2016
Incorporation of minor changes in the structure of a single β,γ-diaminoester linear scaffold resu... more Incorporation of minor changes in the structure of a single β,γ-diaminoester linear scaffold resulted in selective hits for TRPV1, TRPM8 and TRPA1 blockade, as well as some dual antagonists.
Chalcones as positive allosteric modulators of α7 nicotinic acetylcholine receptors: A new target for a privileged structure
European Journal of Medicinal Chemistry, 2014
ACS Combinatorial Science, 2014
PLoS ONE, 2014
Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We rep... more Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry.
Econazole is an anti-mycotic agent widely used for the treatment of cutaneous fungal infections, ... more Econazole is an anti-mycotic agent widely used for the treatment of cutaneous fungal infections, and for the therapy of vaginal candidiasis. Topical application of this azole is generally safe, although some patients have complained of mild burning sensation/cutaneous irritation and itching, especially when administered intravaginally. The underlying mechanisms responsible of these adverse effects are poorly understood, though they suggest excitation of cutaneous nociceptor terminals. We report that exposure of primary cultures of rat nociceptors to econazole augments neuronal excitability. This effect appears mediated by increments in the intracellular Ca2+ by stimulating Ca2+ entry and release from the endoplasmic reticulum. Ca2+ entry was not due to activation of thermo transient receptor potential (TRP) channels, suggesting a different ion channel targeted by the azole. Noteworthy, econazole-evoked responses were potentiated by a pro-inflammatory agent, which resulted in an increase in neuronal excitability. Econazole-elicited action potential firing was significantly abolished by the inflammatory cytokine inhibiting drug benzydamine via blockade of voltage-gated Na+ (Nav) channels. Collectively, our results indicate that the burning sensation of econazole is due at least in part to modulation of nociceptor excitability, and such sensation is increased in the presence of pro-inflammatory stimuli and blocked by benzydamine. These findings imply that a combination of the azole with benzydamine has the potential to reduce significantly the unpleasant symptoms related to infection and to the adverse effects of topical econazole formulations.
Nicotine acethylcholine receptors (nAChRs) play critical roles in cognitive processes, neuroprot... more Nicotine acethylcholine receptors (nAChRs) play critical roles in cognitive processes, neuroprotection and inflammation.
Results: According to their substituents, 1,3-diphenylpropan-1-one derivatives act as α7 nAChRs negative allosteric modulators (NAM, OMe) or Type I positive allosteric modulators (PAMs, OH). Compounds 7 and 31 were the most effective (989 and 666% enhancement of ACh-induced currents) and potent (EC50: 12.9 and 6.85 μM) PAMs. They exhibited strong radical scavenging values. Compound 31, selective over other neuronal nAChR subtypes and with acceptable pharmacokinetic profile, showed antinociceptive effects in a model of
inflammatory pain.
Conclusion: Compound 31 is a novel, potent and selective α7
nAChR PAM, displaying antioxidant and analgesic activities. The 1,3-diphenylpropan-1-one scaffold could be the base toward more advanced type I PAMs for the treatment of nAChR-mediated diseases.
Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is curre... more Pharmacological modulation of the transient receptor potential melastatin type 8 (TRPM8) is currently under investigation as a new approach for the treatment of pain and other diseases. In this study, a series of N-substituted tryptamines was prepared to explore the structural requirements determining TRPM8 modulation. Using a fluorescence-based screening assay, we identified two compounds acting as an activator (2-(1H-indol-3-yl)-N-(4-phenoxybenzyl) ethanamine, 21) or an inhibitor (N,N-dibenzyl-2-(1H-indol-3-yl) ethanamine, 12) of calcium influx in HEK293 cells. In patch-clamp recordings, compound 21 displayed a significantly higher potency (EC 50 = 40±4 µM) and a similar efficacy when compared to menthol; by contrast, compound 12 produced a concentrationdependent inhibition of menthol-induced TRPM8 currents (IC 50 =367±24 nM). Molecular modelling studies using a homology model of a single rat TRPM8 subunit identified a putative binding site located between the VSD and the TRP box, disclosing differences in the binding modes for the agonist and the antagonist.
A high throughput screening campaign identified nine b,g-diamino ester derivatives as TRP modulat... more A high throughput screening campaign identified nine b,g-diamino ester derivatives as TRP modulators. A
discrete library of new derivatives (23 components) was prepared in a one-pot two step reductive amination
reaction, and evaluated for their ability to block the agonist-induced calcium influx in cells expressing
human TRPV1, TRPM8 and TRPA1 channels. Selective antagonists for each channel, as well as dual
TRPV1/TRPM8 and TRPM8/TRPA1 ligands, were obtained after subtle modification of this linear scaffold.
SAR studies revealed the preferred substituents for the selective blockade of the three TRP channels
under study. The most potent TRPV1 antagonists displayed submicromolar IC50 values.
Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We rep... more Paracetamol also known as acetaminophen, is a widely used analgesic and antipyretic agent. We report the synthesis and biological evaluation of adamantyl analogues of paracetamol with important analgesic properties. The mechanism of nociception of compound 6a/b, an analog of paracetamol, is not exerted through direct interaction with cannabinoid receptors, nor by inhibiting COX. It behaves as an interesting selective TRPA1 channel antagonist, which may be responsible for its analgesic properties, whereas it has no effect on the TRPM8 nor TRPV1 channels. The possibility of replacing a phenyl ring by an adamantyl ring opens new avenues in other fields of medicinal chemistry.
Thea7 acetylcholine nicotine receptor is a ligand-gated ion channel that is involved in cognition... more Thea7 acetylcholine nicotine receptor is a ligand-gated ion channel that is involved in cognition dis-orders, schizophrenia, pain and inflammation among other diseases. Therefore, the development of new
agents that target this receptor has great significance. Positive allosteric modulators might be advan-tageous, since they facilitate receptor responses without directly interacting with the agonist binding
site. Here we report the search for and further design of new positive allosteric modulators having the
relatively simple chalcone structure. From the natural product isoliquiritigenin as starting point, chal-cones substituted with hydroxyl groups at defined locations were identified as optimal and specific
promoters ofa7 nicotinic function. The most potent compound (2,4,2
0
,5
0
-tetrahydroxychalcone,111)was
further characterized showing its potential as neuroprotective, analgesic and cognitive enhancer,
opening the way for future developments around the chalcone structure.
Protein-protein interactions (PPIs) have emerged as important targets for pharmaceutical interven... more Protein-protein interactions (PPIs) have emerged as important targets for pharmaceutical intervention because of their essential role in numerous physiological and pathological processes, but screening efforts using small-molecules have led to very low hit rates. Linear peptides could represent a quick and effective approach to discover initial PPI hits, particularly if they have inherent ability to adopt specific peptide secondary structures. Here, we address this hypothesis through a linear helical peptide library, composed of four sublibraries, which was designed by theoretical predictions of helicity (Agadir software). The 13-mer peptides of this collection fixes either a combination of three aromatic or two aromatic and one aliphatic residues on one face of the helix (Ac-SSEEX(5)ARNX(9)AAX(12)N-NH2), since these are structural features quite common at PPIs interfaces. The 81 designed peptides were conveniently synthesized by parallel solid-phase methodologies, and the tendency of some representative library components to adopt the intended secondary structure was corroborated through CD and NMR experiments. As proof of concept in the search for PPI modulators, the usefulness of this library was verified on the widely studied p53-MDM2 interaction and on the communication between VEGF and its receptor Flt-1, two PPIs for which a hydrophobic α-helix is essential for the interaction. We have demonstrated here that, in both cases, selected peptides from the library, containing the right hydrophobic sequence of the hot-spot in one of the protein partners, are able to interact with the complementary protein. Moreover, we have discover some new, quite potent inhibitors of the VEGF-Flt-1 interaction, just by replacing one of the aromatic residues of the initial F(5)Y(9)Y(12) peptide by W, in agreement with previous results on related antiangiogenic peptides. Finally, the HTS evaluation of the full collection on thermoTRPs has led to a few antagonists of TRPV1 and TRPA1 channels, which open new avenues on the way to innovative modulators of these channels.
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Papers by Roberto de la Torre-Martinez
Results: According to their substituents, 1,3-diphenylpropan-1-one derivatives act as α7 nAChRs negative allosteric modulators (NAM, OMe) or Type I positive allosteric modulators (PAMs, OH). Compounds 7 and 31 were the most effective (989 and 666% enhancement of ACh-induced currents) and potent (EC50: 12.9 and 6.85 μM) PAMs. They exhibited strong radical scavenging values. Compound 31, selective over other neuronal nAChR subtypes and with acceptable pharmacokinetic profile, showed antinociceptive effects in a model of
inflammatory pain.
Conclusion: Compound 31 is a novel, potent and selective α7
nAChR PAM, displaying antioxidant and analgesic activities. The 1,3-diphenylpropan-1-one scaffold could be the base toward more advanced type I PAMs for the treatment of nAChR-mediated diseases.
discrete library of new derivatives (23 components) was prepared in a one-pot two step reductive amination
reaction, and evaluated for their ability to block the agonist-induced calcium influx in cells expressing
human TRPV1, TRPM8 and TRPA1 channels. Selective antagonists for each channel, as well as dual
TRPV1/TRPM8 and TRPM8/TRPA1 ligands, were obtained after subtle modification of this linear scaffold.
SAR studies revealed the preferred substituents for the selective blockade of the three TRP channels
under study. The most potent TRPV1 antagonists displayed submicromolar IC50 values.
agents that target this receptor has great significance. Positive allosteric modulators might be advan-tageous, since they facilitate receptor responses without directly interacting with the agonist binding
site. Here we report the search for and further design of new positive allosteric modulators having the
relatively simple chalcone structure. From the natural product isoliquiritigenin as starting point, chal-cones substituted with hydroxyl groups at defined locations were identified as optimal and specific
promoters ofa7 nicotinic function. The most potent compound (2,4,2
0
,5
0
-tetrahydroxychalcone,111)was
further characterized showing its potential as neuroprotective, analgesic and cognitive enhancer,
opening the way for future developments around the chalcone structure.