The Experts below are selected from a list of 2067 Experts worldwide ranked by ideXlab platform

Shitij Kapur - One of the best experts on this subject based on the ideXlab platform.

  • differential effects of aripiprazole on d 2 5 ht 2 and 5 ht 1a receptor occupancy in patients with schizophrenia a triple tracer pet study
    American Journal of Psychiatry, 2007
    Co-Authors: David C Mamo, Chekkera Shammi, Ariel Graff, Romina Mizrahi, Francoise Romeyer, Shitij Kapur
    Abstract:

    Objective: Aripiprazole has a unique pharmacological profile that includes Partial Agonism at D 2 receptors, antAgonism at 5-HT 2 receptors, and Partial Agonism at 5-HT 1A receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D 2 , 5-HT 2 , and 5-HT 1A receptors in patients with schizophrenia or schizoaffective disorder. Method: Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [ 11 C]raclopride, [ 18 F]setoperone, and [ 11 C]WAY100635. Results: Very high occupancy was observed at striatal D 2 receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT 2 receptors (54%–60%), and even lower occupancy at 5-HT 1A receptors (16%). D 2 occupancy levels were significantly correlated with plasma drug c...

  • differential effects of aripiprazole on d 2 5 ht 2 and 5 ht 1a receptor occupancy in patients with schizophrenia a triple tracer pet study
    American Journal of Psychiatry, 2007
    Co-Authors: David C Mamo, Chekkera Shammi, Ariel Graff, Romina Mizrahi, Francoise Romeyer, Shitij Kapur
    Abstract:

    OBJECTIVE: Aripiprazole has a unique pharmacological profile that includes Partial Agonism at D(2) receptors, antAgonism at 5-HT(2) receptors, and Partial Agonism at 5-HT(1A) receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder. METHOD: Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [(11)C]raclopride, [(18)F]setoperone, and [(11)C]WAY100635. RESULTS: Very high occupancy was observed at striatal D(2) receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT(2) receptors (54%-60%), and even lower occupancy at 5-HT(1A) receptors (16%). D(2) occupancy levels were significantly correlated with plasma drug concentrations, and even the lowest dose (10 mg) led to 85% D(2) occupancy. Extrapyramidal side effects were seen only in two of the four participants with occupancies exceeding 90%. CONCLUSIONS: Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT(2) occupancy is lower than D(2) occupancy. Implications for aripiprazole's mechanism of action are discussed.

David C Mamo - One of the best experts on this subject based on the ideXlab platform.

  • differential effects of aripiprazole on d 2 5 ht 2 and 5 ht 1a receptor occupancy in patients with schizophrenia a triple tracer pet study
    American Journal of Psychiatry, 2007
    Co-Authors: David C Mamo, Chekkera Shammi, Ariel Graff, Romina Mizrahi, Francoise Romeyer, Shitij Kapur
    Abstract:

    Objective: Aripiprazole has a unique pharmacological profile that includes Partial Agonism at D 2 receptors, antAgonism at 5-HT 2 receptors, and Partial Agonism at 5-HT 1A receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D 2 , 5-HT 2 , and 5-HT 1A receptors in patients with schizophrenia or schizoaffective disorder. Method: Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [ 11 C]raclopride, [ 18 F]setoperone, and [ 11 C]WAY100635. Results: Very high occupancy was observed at striatal D 2 receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT 2 receptors (54%–60%), and even lower occupancy at 5-HT 1A receptors (16%). D 2 occupancy levels were significantly correlated with plasma drug c...

  • differential effects of aripiprazole on d 2 5 ht 2 and 5 ht 1a receptor occupancy in patients with schizophrenia a triple tracer pet study
    American Journal of Psychiatry, 2007
    Co-Authors: David C Mamo, Chekkera Shammi, Ariel Graff, Romina Mizrahi, Francoise Romeyer, Shitij Kapur
    Abstract:

    OBJECTIVE: Aripiprazole has a unique pharmacological profile that includes Partial Agonism at D(2) receptors, antAgonism at 5-HT(2) receptors, and Partial Agonism at 5-HT(1A) receptors. The authors conducted a positron emission tomography (PET) study to characterize the simultaneous effects of aripiprazole at the D(2), 5-HT(2), and 5-HT(1A) receptors in patients with schizophrenia or schizoaffective disorder. METHOD: Twelve patients who had previously received antipsychotic treatment were randomly assigned to receive 10 mg, 15 mg, 20 mg, or 30 mg of aripiprazole. After at least 14 days of treatment, participants underwent high-resolution PET scans using [(11)C]raclopride, [(18)F]setoperone, and [(11)C]WAY100635. RESULTS: Very high occupancy was observed at striatal D(2) receptors (average putamen, 87%; caudate, 93%; and ventral striatum, 91%), lower occupancy at 5-HT(2) receptors (54%-60%), and even lower occupancy at 5-HT(1A) receptors (16%). D(2) occupancy levels were significantly correlated with plasma drug concentrations, and even the lowest dose (10 mg) led to 85% D(2) occupancy. Extrapyramidal side effects were seen only in two of the four participants with occupancies exceeding 90%. CONCLUSIONS: Aripiprazole exhibits a unique occupancy profile as compared with other conventional and atypical antipsychotics. The threshold for response appears to be higher than 60%, extrapyramidal side effects appear to be uncommon even at occupancies that exceed the conventional extrapyramidal side effects threshold of 80%, and 5-HT(2) occupancy is lower than D(2) occupancy. Implications for aripiprazole's mechanism of action are discussed.

Francesco Bavo - One of the best experts on this subject based on the ideXlab platform.

  • modifications at c 5 of 2 2 pyrrolidinyl substituted 1 4 benzodioxane elicit potent α4β2 nicotinic acetylcholine receptor Partial Agonism with high selectivity over the α3β4 subtype
    Journal of Medicinal Chemistry, 2020
    Co-Authors: Francesco Bavo, Cecilia Gotti, M Pallavicini, Rebecca Appiani, Milena Moretti, Sara Francesca Colombo, Susanna Pucci, P Viani, Roberta Budriesi, Massimiliano Renzi
    Abstract:

    A series of diastereomeric 2-(2-pyrrolidinyl)-1,4-benzodioxanes bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position of benzodioxane have been studied for α4β2 and α3β4 nicotinic acetylcholine receptor affinity and activity. Analogous to C(5)H replacement with N and to a much greater extent than decoration at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4 selectivity to the α4β2 Partial Agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus β2 side converge in indicating that the limited accommodation capacity of the β2 pocket, compared to that of the β4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.

  • from pyrrolidinyl benzodioxane to pyrrolidinyl pyridodioxanes or from unselective antAgonism to selective Partial Agonism at α4β2 nicotinic acetylcholine receptor
    European Journal of Medicinal Chemistry, 2017
    Co-Authors: Cristiano Bolchi, Francesco Bavo, Cecilia Gotti, Laura Fumagalli, Francesca Fasoli, Matteo Binda, Vanessa Mucchietto, Miriam Sciaccaluga, Simona Plutino, Sergio Fucile
    Abstract:

    Each of the four aromatic -CH= of (S,R)-2-pyrrolidinyl-1,4-benzodioxane [(S,R)-6] and of its epimer at the dioxane stereocenter (S,S)-6, previously reported as α4β2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at α4β2, α3β4 and α7 nAChR subtypes and compared to their common carbaisostere. It turned out that such isosteric substitutions are highly detrimental, but with the important exception of the S,R stereoisomer of the pyrrolidinyl-pyridodioxane with the pyridine nitrogen adjacent to the dioxane and seven atoms distant from the pyrrolidine nitrogen. Indeed, this stereo/regioisomer not only maintained the α4β2 affinity of [(S,R)-6], but also greatly improved in selectivity over the α3β4 and α7 subtypes and, most importantly, exhibited a highly selective α4β2 Partial Agonism. The finding that [(S,R)-6] is, instead, an unselective α4β2 antagonist indicates that the benzodioxane substructure confers affinity for the α4β2 nAChR binding site, but activation of this receptor subtype needs benzodioxane functionalization under strict steric requirements, such as the previously reported 7-OH substitution or the present isosteric modification.

Massimiliano Renzi - One of the best experts on this subject based on the ideXlab platform.

  • modifications at c 5 of 2 2 pyrrolidinyl substituted 1 4 benzodioxane elicit potent α4β2 nicotinic acetylcholine receptor Partial Agonism with high selectivity over the α3β4 subtype
    Journal of Medicinal Chemistry, 2020
    Co-Authors: Francesco Bavo, Cecilia Gotti, M Pallavicini, Rebecca Appiani, Milena Moretti, Sara Francesca Colombo, Susanna Pucci, P Viani, Roberta Budriesi, Massimiliano Renzi
    Abstract:

    A series of diastereomeric 2-(2-pyrrolidinyl)-1,4-benzodioxanes bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position of benzodioxane have been studied for α4β2 and α3β4 nicotinic acetylcholine receptor affinity and activity. Analogous to C(5)H replacement with N and to a much greater extent than decoration at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4 selectivity to the α4β2 Partial Agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus β2 side converge in indicating that the limited accommodation capacity of the β2 pocket, compared to that of the β4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.

Cecilia Gotti - One of the best experts on this subject based on the ideXlab platform.

  • modifications at c 5 of 2 2 pyrrolidinyl substituted 1 4 benzodioxane elicit potent α4β2 nicotinic acetylcholine receptor Partial Agonism with high selectivity over the α3β4 subtype
    Journal of Medicinal Chemistry, 2020
    Co-Authors: Francesco Bavo, Cecilia Gotti, M Pallavicini, Rebecca Appiani, Milena Moretti, Sara Francesca Colombo, Susanna Pucci, P Viani, Roberta Budriesi, Massimiliano Renzi
    Abstract:

    A series of diastereomeric 2-(2-pyrrolidinyl)-1,4-benzodioxanes bearing a small, hydrogen-bonding substituent at the 7-, 6-, or 5-position of benzodioxane have been studied for α4β2 and α3β4 nicotinic acetylcholine receptor affinity and activity. Analogous to C(5)H replacement with N and to a much greater extent than decoration at C(7), substitution at benzodioxane C(5) confers very high α4β2/α3β4 selectivity to the α4β2 Partial Agonism. Docking into the two receptor structures recently determined by cryo-electron microscopy and site-directed mutagenesis at the minus β2 side converge in indicating that the limited accommodation capacity of the β2 pocket, compared to that of the β4 pocket, makes substitution at C(5) rather than at more projecting C(7) position determinant for this pursued subtype selectivity.

  • from pyrrolidinyl benzodioxane to pyrrolidinyl pyridodioxanes or from unselective antAgonism to selective Partial Agonism at α4β2 nicotinic acetylcholine receptor
    European Journal of Medicinal Chemistry, 2017
    Co-Authors: Cristiano Bolchi, Francesco Bavo, Cecilia Gotti, Laura Fumagalli, Francesca Fasoli, Matteo Binda, Vanessa Mucchietto, Miriam Sciaccaluga, Simona Plutino, Sergio Fucile
    Abstract:

    Each of the four aromatic -CH= of (S,R)-2-pyrrolidinyl-1,4-benzodioxane [(S,R)-6] and of its epimer at the dioxane stereocenter (S,S)-6, previously reported as α4β2 nAChR ligands, was replaced with nitrogen. The resulting four diastereoisomeric pairs of pyrrolidinyl-pyridodioxanes were studied for the nicotinic affinity and activity at α4β2, α3β4 and α7 nAChR subtypes and compared to their common carbaisostere. It turned out that such isosteric substitutions are highly detrimental, but with the important exception of the S,R stereoisomer of the pyrrolidinyl-pyridodioxane with the pyridine nitrogen adjacent to the dioxane and seven atoms distant from the pyrrolidine nitrogen. Indeed, this stereo/regioisomer not only maintained the α4β2 affinity of [(S,R)-6], but also greatly improved in selectivity over the α3β4 and α7 subtypes and, most importantly, exhibited a highly selective α4β2 Partial Agonism. The finding that [(S,R)-6] is, instead, an unselective α4β2 antagonist indicates that the benzodioxane substructure confers affinity for the α4β2 nAChR binding site, but activation of this receptor subtype needs benzodioxane functionalization under strict steric requirements, such as the previously reported 7-OH substitution or the present isosteric modification.