Novel 3-iodo-8-ethoxypyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide as promising lead for design of alpha5-inverse agonist useful tools for therapy of mnemonic damage

Gabriella Guerrini; Giovanna Ciciani; Giovanni Cambi; Fabrizio Bruni; Silvia Selleri; François Besnard; Marina Montali; Claudia Martini; Carla Ghelardini; Nicoletta Galeotti; Annarella Costanzo

doi:10.1016/j.bmc.2007.01.053

Novel 3-iodo-8-ethoxypyrazolo[5,1-c][1,2,4]benzotriazine 5-oxide as promising lead for design of alpha5-inverse agonist useful tools for therapy of mnemonic damage

Bioorg Med Chem. 2007 Apr 1;15(7):2573-86. doi: 10.1016/j.bmc.2007.01.053. Epub 2007 Feb 2.

Authors

Gabriella Guerrini¹, Giovanna Ciciani, Giovanni Cambi, Fabrizio Bruni, Silvia Selleri, François Besnard, Marina Montali, Claudia Martini, Carla Ghelardini, Nicoletta Galeotti, Annarella Costanzo

Affiliation

¹ Dipartimento di Scienze Farmaceutiche, Università degli Studi di Firenze, Via U. Schiff, 6, 50019 Polo Scientifico, Sesto Fiorentino (Firenze), Italy. [email protected]

PMID: 17306981
DOI: 10.1016/j.bmc.2007.01.053

Abstract

The synthesis and the binding study of new 3-iodiopyrazolo[5,1-c][1,2,4] benzotriazine 5-oxides 8-alkyloxy substituted are reported. The replacement at position 3 with an iodine atom, with respect to substituents capable to form a three centered hydrogen bond and/or to form pi-pi stacking interaction with receptor protein, gave high affinity ligands, independently of the 8-alkyloxy substituent. High-affinity ligands were studied in mice in vivo for their pharmacological effects, considering five potential benzodiazepine actions: anxiolytic-like effects, motor coordination, anticonvulsant action, mouse learning and memory impairment, and ethanol-potentiating action. Compounds 5c and 5'c have an inverse agonist profile and for the first time is evidenced a pro-mnemonic activity. These compounds were evaluated also for their binding at Benzodiazepine site on GABA(A) receptor complex (GABA(A)/BzR complex) subtype to evaluate their subtype selectivity.

MeSH terms

Animals
Anti-Anxiety Agents / pharmacology
Anxiety / drug therapy
Anxiety / psychology
Ataxia / chemically induced
Ataxia / psychology
Diazepam / pharmacology
Drug Design
GABA Agonists / pharmacology
Hand Strength
Indicators and Reagents
Learning / drug effects
Ligands
Male
Memory Disorders / drug therapy*
Memory, Short-Term / drug effects
Mice
Nootropic Agents / chemical synthesis*
Nootropic Agents / metabolism
Nootropic Agents / pharmacology*
Postural Balance / drug effects
Pyrazoles / chemical synthesis*
Pyrazoles / pharmacology
Rats
Rats, Wistar
Receptors, GABA-A / drug effects
Seizures / chemically induced
Seizures / prevention & control
Sleep / drug effects
Triazines / chemical synthesis*
Triazines / pharmacology
gamma-Aminobutyric Acid / metabolism

Substances

3-iodo-8-ethoxypyrazolo(5,1-c)(1,2,4)benzotriazine 5-oxide
Anti-Anxiety Agents
GABA Agonists
Indicators and Reagents
Ligands
Nootropic Agents
Pyrazoles
Receptors, GABA-A
Triazines
gamma-Aminobutyric Acid
Diazepam