A Boehringer Ingelheim SFN paper -
>>> Program#/Poster#: 267.2/GG19
Title: Effects of the positive allosteric AMPA receptor modulator BIIR 777: In vitro and in vivo studies
Location: Georgia World Congress Center: Halls B3-B5
Presentation Start/End Time: Sunday, Oct 15, 2006, 2:00 PM - 3:00 PM
Authors: *T. WEISER1, K. WINTER2, K. KLINDER3, T. OSUGI4, A. CECI1;
1CNS Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, GERMANY, 2Quality Operations, Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim, GERMANY, 3Drug Discovery Support, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, GERMANY, 4R&D Project Management, Boehringer Ingelheim US, Rigdefield, CT.
Positive modulation of AMPA-receptor mediated neurotransmission is a promising approach for the treatment of disorders affecting learning and memory. Here we describe the effects of BIIR 777, a novel and selective AMPA receptor modulator. In patch-clamp experiments using rat cortical neurons, or cells transfected with human GluR1/2, BIIR 777 significantly reduced desensitisation at concentrations >1 µM without affecting agonist potency. Investigating selectivity in >65 binding assays showed that the compound was highly selective. In anaesthetised rats, the excitatory local effect of AMPA on electrical activity of CA1 pyramidal hippocampal neurons was significantly increased in response to iontophoretic coadministration with BIIR 777. The systemic administration of BIIR 777 increased firing frequencies of pyramidal neurons in the CA1 region of the hippocampus, as well as in prefrontal cortex (CG3; at doses of 0.1 to 0.3 mg/kg i.v.). Pharmakokinetic investigations showed that BIIR 777 was orally available, penetrated the blood-brain barrier well, and had a plasma halflife of 8.5 h after oral administration. Thus, this compound was suitable for further in vivo models of learning and memory. In the passive avoidance test in rats, 30 mg/kg p.o. significantly reduced the proamnesic effect of alprazolam (0.45 mg/kg i.p.). In the rat object recognition test, BIIR 777 significantly augmented memory at 3, 10, and 30 mg/kg p.o.
These data show that BIIR 777 is a potent positive allosteric modulator of AMPA receptor function with promising properties in models of learning and memory in vivo. <<<
