4WD to Travel Inside the 5-HT1A Receptor World

Abstract

5-HT 1A receptor is one of the most important members of the numerous families of serotoninergic receptors. Though it was the first 5-HT receptor to be identified and cloned, the knowledge of its activation/transduction mechanisms, mediated effects, and connection with other systems is still uncompleted. For this reason, relevant is the study of the four Ws of the title: first of all "who" this receptor is, then "why" it continues to be a so attractive target after several years after its identification, then "where" is 5-HT 1A receptor expressed within the body, and, finally, "what" effects this receptor can elicit under physiological and pathological conditions. Obviously, more and more potent, safe, and selective "drugs" might be discovered once the responses to these questions are given.

Design, Synthesis and Biological Evaluation of Novel N-Arylpiperazines Containing a 4,5-Dihydrothiazole Ring

“…Mechanistically, almost all of them act as agonists (partial/full) of 5-HT 1A R, and two main interactions proved to be important for the affinity of arylpiperazines toward 5-HT 1A Rs: (a) an ionic bond between the protonated nitrogen atom of the piperazine ring and the carboxyl oxygen of the side chain of Asp3.32 and (b) an edge-to-face CH/π interaction between the aromatic ring and the Phe6.52 residue, which stabilizes the ligand binding [6]. The basic pharmacophore of the 5-HT 1A R ligands is the same for agonists and antagonists and consists of an aromatic nucleus and a basic nitrogen atom, whose optimal distance is 5.2 Å, while the nitrogen lies at 0.2 Å above the plane defined by the reference ring [7]. Moreover, arylpiperazine derivatives have been described to reduce prostate cancer cell growth [8] and to ameliorate sensitivity to Tamoxifen in ER+ BC cells [4].…”