ARTICLE
pubs.acs.org/jmc
New Insight into the Central Benzodiazepine ReceptorÀLigand
Interactions: Design, Synthesis, Biological Evaluation, and Molecular
Modeling of 3-Substituted 6-Phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and Related Compounds†
Maurizio Anzini,*,‡ Salvatore Valenti,‡ Carlo Braile,‡ Andrea Cappelli,*,‡ Salvatore Vomero,‡ Stefano Alcaro,§
Francesco Ortuso,§ Luciana Marinelli,|| Vittorio Limongelli,|| Ettore Novellino,|| Laura Betti,^
Gino Giannaccini,^ Antonio Lucacchini,^ Simona Daniele,^ Claudia Martini,^ Carla Ghelardini,#
Lorenzo Di Cesare Mannelli,# Gianluca Giorgi,∞ Maria Paola Mascia,b,1 and Giovanni Biggiob,1
‡
)
Dipartimento Farmaco Chimico Tecnologico and European Research Centre for Drug Discovery and Development,
Universit degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
a
§
Dipartimento di Scienze Farmacobiologiche, Universit “Magna Græcia” di Catanzaro, Complesso Nin Barbieri, 88021 Roccelletta di
a
i
Borgia (CZ), Italy
Dipartimento di Chimica Farmaceutica e Tossicologica, Universit di Napoli “Federico II”, Via D. Montesano 49, 80131 Napoli, Italy
a
^
Dipartimento di Psichiatria, Neurobiologia Farmacologia e Biotecnologie, Universit di Pisa, Via Bonanno 6, 56126 Pisa, Italy
a
#
Dipartimento di Farmacologia Preclinica e Clinica “M. Aiazzi Mancini”, Universit degli Studi di Firenze, Viale G. Pieraccini 6,
a
50139 Firenze, Italy
∞
Dipartimento di Chimica, Universit degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
a
b
Dipartimento di Biologia Sperimentale “B. Loddo”, Sezione Neuroscienze, Universit degli Studi di Cagliari, Cittadella Universitaria,
a
S.S. 554, Km. 4.500, 09042 Monserrato (CA), Italy
1
Istituto di Neuroscienze, Consiglio Nazionale delle Ricerche, Cittadella Universitaria, S.S. 554, Km 4.500, 09042 Monserrato (CA), Italy
S
b Supporting Information
ABSTRACT: 3-Substituted 6-phenyl-4H-imidazo[1,5-a][1,4]benzodiazepines and related compounds were synthesized as central benzodiazepine receptor (CBR) ligands. Most of the
compounds showed high affinity for bovine and human CBR, their Ki values spanning from the
low nanomolar to the submicromolar range. In particular, imidazoester 5f was able to promote a
massive flow of 36ClÀ in rat cerebrocortical synaptoneurosomes overlapping its efficacy profile
with that of a typical full agonist. Compound 5f was then examined in mice for its
pharmacological effects where it proved to be a safe anxiolytic agent devoid of the unpleasant
myorelaxant and amnesic effects of the classical 1,4-benzodiazepines. Moreover, the selectivity
of some selected compounds has been assessed in recombinant R1β2γ2L, R2β1γ2L, and
R5β2γ2L human GABAA receptors. Finally, some compounds were submitted to molecular
docking calculations along with molecular dynamics simulations in the Cromer’s GABAA
homology model.
’ INTRODUCTION
The action of γ-aminobutyric acid (GABA) on the GABAA
chloride channel complex is capable of controlling the excitability
of many central nervous system
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