Premium
P4–438: Histamine H3 receptor antagonists elicit procognitive effects on episodic and spatial reference memories of young and aged animals
Author(s) -
Rowe Wayne,
Di Somma Rachael,
Hsu Cathleen,
Solomon Ken,
Callahan Patrick,
Wang Daguang,
Lowe David
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.2180
Subject(s) - thioperamide , neurochemical , histamine h3 receptor , psychology , histamine , antagonist , morris water navigation task , neuroscience , working memory , histamine receptor , medicine , endocrinology , receptor , cognition
properly; as they age, or are affected by toxins such as beta amyloid peptides, neurons lose this ability. An increase in Ca entry into the cell alters activity of Ca -dependent proteins such as ion channels and proteolytic enzymes which may adversely affect many cell functions. Excessive Ca entry may be exacerbated by an increase in density of L-type Ca -channels reported to occur in aging and in Alzheimer’s disease. Blocking voltage-regulated calcium channels may facilitate the ability of neurons to maintain appropriate calcium levels and function properly. Memory Pharmaceuticals is developing MEM1003, a dihydropyridine (DHP) Ca channel modulator, for Alzheimer’s disease. MEM1003 is equipotent to nimodipine, another DHP, in blocking L-type Ca currents in CA1 hippocampal neurons, but it is 4 to 15-fold less potent in relaxing rat thoracic smooth muscle when compared to other DHPs like nimodipine, nitrendipine or felodipine. This suggests that MEM1003 may have a superior safety profile. MEM1003 is a single enantiomer, unlike nimodipine and many other DHP drugs, and may lack potential off-target pharmacological activities present in racemic mixtures. We will present data showing the effectiveness of MEM1003 in improving cognitive performance in multiple preclinical behavior models at plasma exposure levels consistent with its affinity for the DHP binding site. One proposed mechanism for the procognitive effects of MEM1003 is that it mediates a reduction in the slow afterhypolarization (sAHP) of CA1 pyramidal neurons. An enlarged sAHP, functionally linked to L-type Ca channels, may interfere with cognitive behaviors. Our recent findings have demonstrated that sAHP amplitude co-varies with spatial learning ability in aged rats (Tombaugh et al., 2005). The pharmacokinetic and safety profiles of MEM1003 were recently studied in double-blind, randomized, placebocontrolled Phase 1A and Phase 1B clinical trials. MEM1003 was well tolerated up to the highest dose tested of 180 mg twice daily. The safety data and pharmacokinetics of MEM1003 in these studies will be presented and the relevance of the exposure levels to preclinical animal efficacy models and toxicology studies will be discussed. MEM1003 is currently in a Phase 2A clinical trial for Alzheimer’s disease.