Computational study of the alpha1-Adrenoceptor subtypes and their ligands

Abstract

Adrenoceptors (AR) belong to the G-protein coupled receptor (GPCR) family. These receptors play an important role in regulating many processes in the body related to the central nervous system, vascular system and many others. The importance of these receptors as regulators can be further stressed as they are considered promising drug targets. Currently 40 % of all marketed drugs are targeted at GPCRs. The adrenoceptors can be subdivided into nine different classes of which the α1-AR class consists of three subtypes (α14-AR, α1B-AR and α1D-AR). This α1-AR class plays an important role in the condition known as benign prostatic hyperplasia (BPH). BPH affects 50% of men over 50 years old and with the aging of the population percentage, this percentage is expected to rise. BPH is manifested by the enlargem ent of prostate tissue that constrains the urethra Prostatic smooth muscle contraction occurs mainly via the α1A-AR subtype. The effect of BPH is manifested through the impaired flow of urine through the urethra when is passes the prostate. Inhibition of the α1A-AR by using an antagonist has shown to increase the urine flow and therefore, decrease the physiological aspects of BPH. The class α1D-AR is located in the neck of the bladder where the urine leaves the bladder and it is believed that inhibiting this receptor could be beneficial in the treatment of BPH. The α1B-AR does not play a role related to BPH, but is present in the brain. Therefore, it is believed that inhibition of this receptor could result in unwanted side-effects. Hence, antagonists which are selective for the α1A-AR and α1D-AR would be useful for treating BPH with reduced side effects. In our research we develop models for each of the three α1-AR subtypes which can be used in determining ligand-specific interaction with each subtype.