Luisa Materia

Novel 4-Phenylpiperidine-2,6-Dione Derivatives. Ligands for α1-Adrenoceptor Subtypes

A number of new 4-phenylpiperidine-2,6-diones bearing at the 1-position an ω-[4-(substituted phenyl)piperazin-1-yl]alkyl moiety were designed and synthesized as ligands for the α(1)-adrenergic receptor (α(1)-AR) subtypes. Some synthesized compounds, tested in binding assays for the human cloned α(1A)-, α(1B)-, and α(1D)-AR subtypes, displayed affinities in the nanomolar range. Highest affinity values were found in derivatives having a butyl connecting chain between the 4-phenylpiperidine-2,6-dione and the phenylpiperazinyl moieties. 1-[4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl]-4-phenylpiperidine-2,6-dione (34) showed the best affinity for the α(1A)-AR (pK(i) = 8.74) and 10-fold selectivity compared to the other two α(1)-AR subtypes. Some representative compounds were also tested in order to evaluate their effects on the signal transduction pathway coupled to α(1)-AR subtypes. They all blocked norepinephrine-induced stimulation of inositol phospholipid hydrolysis, thus behaving as antagonists. Binding data were used to refine a previously developed pharmacophoric model for α(1D)-ARs. The revised model shows a highly predictive power and could be useful for the future design of high affinity α(1D)-AR ligands.

Novel antagonists for α1-adrenoceptor subtypes

α1-Adrenergic receptors (α1-ARs) belong to the seven-transmembrane-domain receptor superfamily and play a primary role in the regulation of several physiological processes, particularly in the cardiovascular system. Three different α1-AR subtypes, namely α1A-AR, α1B-AR and α1D-AR, have been cloned and characterised so far. In the past, several non-subtype-selective α1-AR antagonists, such as prazosin (the prototype of these substances), doxazosin and terazosin, have been used as effective antihypertensive drugs and, more recently, in the symptomatic treatment of benign prostatic hypertrophy (BPH). Intensive research in academia and pharmaceutical industries has led to the discovery of a number of subtype-selective antagonists in the last decade particularly for the α1A-AR, which seems to be the main subtype involved in bladder outlet obstruction in patients with BPH. This review, which is mainly based on the patent literature (2000 – 2003), is focused on the recent advances in the development of new subtype-selective α1-AR antagonists and their potential therapeutic applications.