Leurquin, Fabien; (1999) Non imidazole H3-receptor histamine antagonists. Doctoral thesis (Ph.D), UCL (University College London).

Preview

Text out.pdf Download (17MB) | Preview

Abstract

Histamine is a biogenic amine inducing a range of physiological responses through three receptor subtypes. The role of the presynaptic H3 receptor in the central nervous system is regulatory by way of a negative feedback mechanism. A brain-penetrating H3-receptor antagonist would increase neurotransmission and is likely to have therapeutic applications in the treatment of disorders such as memory and learning deficits, sleep disturbance, epilepsy and Alzheimer's disease. So far, a common feature among H3-receptor ligands is an imidazole ring which is very polar and gives poor lipophilicity. This can be detrimental to brain penetration, hence it is important to design non imidazole antagonists that are less polar in order to increase brain penetration. However, it is thought that the imidazole ring is essential for activity at H3 receptors. By adding an alkyl spacer and a lipophilic group which is thought to reach an additional binding site, we were able to remove the imidazole ring without losing the activity. The aryloxyalkylamines prepared by various known synthetic methods were submitted as salts of an organic or inorganic acid to facilitate their solubility in water. Their biological activity was determined in rodents on brain preparations (in vitro) or given orally to live animals (in vivo). Modifications of the structure of the lead compound and structure-activity studies led to the synthesis of a series of orally active substituted phenoxypropylpiperidines some of which are the most potent non imidazole H3 receptor antagonists described so far. Over 100 novel compounds were prepared and tested for this project. The most active of them is at least twice as potent in vitro and 8 times as active in vivo as the reference H3-receptor antagonist thioperamide. In addition, another series of aryloxyalkylamines as antagonists at the NMDA receptor is investigated.

Download activity - last month

Export as XMLJSONCSV

Download activity - last 12 months

Export as CSVXMLJSON

Downloads by country - last 12 months

Export as CSVJSONXML

Archive Staff Only

View Item