Synthesis and Structure−Activity Relationships of Fused Imidazopyridines:  A New Series of Benzodiazepine Receptor Ligands

Abstract

2-Arylimidazo[4,5-c]quinolines and analogous fused imidazopyridines were synthesized and evaluated as benzodiazepine receptor ligands. Affinity to the receptors was greatly affected by the bulkiness of the aryl group at the 2-position, compared to the pyrazoloquinolines such as CGS-9896. Derivatives with an isoxazole moiety at the 2-position showed high binding affinity and in vivo activity. In the imidazo[4,5-c]quinoline series, substitution at the 6-position decreased or abolished activity. Most derivatives with an unsubstituted isoxazolyl group showed antagonist or inverse agonist activity except for the 7-halo analogues, which exhibited agonist activity. On the other hand, 5-methylisoxazol-3-yl or 3-methylisoxazol-5-yl derivatives generally exhibited agonist activity. A similar substitution effect on the isoxazole moiety was observed in the imidazopyridines fused with a nonaromatic ring. From the detailed pharmacological evaluation, S-8510, 2-(3-isoxazolyl)-3,6,7,9-tetrahydroimidazo[4,5-d]pyrano++ +[4,3-b]pyridine monophosphate, possessing weak inverse agonist activity was selected as a therapeutic candidate for the treatment of some symptoms of senile dementia.

Molecular targets for the rational design of antiepileptic drugs and related neuroprotective agents

“…They comprise a new series of BZD receptor ligands with positive and negative functional effects; new types of anticonvulsants and other related drugs could be envisioned in this structural series. 164 c. Barbiturate Site. This site mediates some of the anesthetic and anticonvulsant actions of barbiturate analogues.…”

3-Aryl-[1,2,4]triazino[4,3-a]benzimidazol-4(10H)-ones: Tricyclic Heteroaromatic Derivatives as a New Class of Benzodiazepine Receptor Ligands

“…To this day, the structure of the BzR remains unresolved. , A wide variety of compounds with a chemical structure different from that of benzodiazepines have been synthesized and tested − to identify BzR ligands displaying high potency and the desired efficacy profile. Among them, the most interesting classes are 2-arylpyrazoloquinolines ( I ), , β-carbolines ( II ), and pyridodiindoles ( III ) .…”

N‘-Phenylindol-3-ylglyoxylohydrazide Derivatives: Synthesis, Structure−Activity Relationships, Molecular Modeling Studies, and Pharmacological Action on Brain Benzodiazepine Receptors

“…The interaction of GABA with its receptor opens the ion channel so that the chloride influx is enhanced, the membrane is hyperpolarized, and the cell becomes less responsive to excitatory stimuli. This GABA-induced ion current can be allosterically regulated by diverse agents, which have specific binding sites on this macromolecular complex. , Of these, compounds which mediate their actions at the benzodiazepine receptor (BzR) are the most widely studied. − Benzodiazepines and several substances with a chemical structure different from that of classic 1,4-benzodiazepines (Bz) bind with a high affinity at the BzR and exhibit a wide variety of pharmacological actions spanning the entire efficacy spectrum. − Full agonists potentiate the GABA-induced chloride influx (positive modulation) decreasing the excitability of the neuron and have found widespread use in the treatment of anxiety and sleep disorders. Inverse agonists decrease the chloride ion influx (negative modulation) and produce proconvulsant, anti-inebriant, and anxiogenic effects.…”

“…[3][4][5] Benzodiazepines and several substances with a chemical structure different from that of classic 1,4-benzodiazepines (Bz) bind with a high affinity at the BzR and exhibit a wide variety of pharmacological actions spanning the entire efficacy spectrum. [6][7][8][9][10][11][12][13][14] Full agonists potentiate the GABA-induced chloride influx (positive modulation) decreasing the excitability of the neuron and have found widespread use in the treatment of anxiety and sleep disorders. Inverse agonists decrease the chloride ion influx (negative modulation) and produce proconvulsant, anti-inebriant, and anxiogenic effects.…”