The pharmacology of the 5-HT2A receptor and the difficulty surrounding functional studies with single target models

QR Microbiology

Steven, Stacy ; Milligan, Graeme

University:University of Glasgow

Department:Institute of Neuroscience and Psychology

关键词: Serotonin, 5-ht2a, schizophrenia, GPCR;   

Others  :  http://theses.gla.ac.uk/3636/1/2012stevenmscr.pdf

来源: University of Glasgow

【 摘 要 】

Treatment of many disorders can be frequently problematic due to the relatively non selective nature of many drugs available on the market. Symptoms can be complex and expansive, often leading to symptoms representing other disorders in addition to the primary reason for treatment. In particular mental health disorders fall prey to this situation. Targeting treatment can be difficult due to the implication of receptors in more than one disorder, and more than one receptor in a single disorder. In the instance of GPCRs, receptors such as the serotonin receptors (and in particular the 5-HT2A for the interest of this research) belong to a large family of receptors, the GPCR Class A super family. Around 50% of the drugs now commercially available target GPCR receptors (Wise et al 2004, Katugampola & Davenport.,2003) and drugs with action at serotonin receptors are used in the treatment of many disorders, particularly psychotic disorders such as schizophrenia. Inability to target single receptors selectively means that the therapeutic values of the drugs are much lower than desired. In this study, the 5-HT2A receptor was incorporated into a stable, inducible cell line using HEK 293 cells and the Flp-in T-REx system, allowing receptor expression to be under the control of the antibiotic doxycycline and hence allow pharmacology to be explored. There is a variation when looking at the potency of agonists in relation to calcium mobilisation and IP-one accumulation, although following the same order of potency the values differ between each experiment type. The order of potency for the majority of the antagonist ligands is very different when looking at IP-one and Ca2+ experiments, as are the values obtained for affinity. This was surprising due to the both lying downstream of the IP3 pathway. The most closely relating results to the published IUPHAR values stem from binding experiments. Understanding the pharmacology of the single receptor by several methods is essential when screening drugs for effectiveness at the receptor. Here the data exploring the pharmacology of the 5-HT2A receptor demonstrated the difficulty surrounding functional studies using single target models.