Synthesis, 5-Hydroxytryptamine_1A Receptor Affinity and Docking Studies of 3-[3-(4-Aryl-1-piperazinyl)-propyl]-1<i>H</i>-Indole Derivatives

Abstract

A series of 3-[3-(4-aryl-1-piperazinyl)-propyl]-1H-indole derivatives (12a-hKey words indolylalkylarylpiperazine; 5-hydroxytryptamine 1A receptor; docking; binding; synthesis Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that mediates various physiological and pathological processes in the peripheral and central nervous system (CNS) by interacting with several different receptors.1-3) The 5-HT 1A receptor sub-population has attracted considerable attention in the drug discovery field.4-7) It is assumed that anxiolytic drugs such as buspirone (1), tandospirone (2), gepirone (3) or ipsapirone (4) (Fig. 1), exert their pharmacological activity through the activation of the 5-HT 1A receptor, where they act as partial agonists.8-10) The 5-HT 1A receptor is also implicated in many other physiopathological CNS processes and conditions such as neuroprotection, schizophrenia, Parkinson's and Alzheimer's diseases, acting alone or associated with other neurotransmitter receptors, especially dopamine receptors.Long-chain arylpiperazine derivatives are one of the most important classes of 5-HT 1A ligands. In general, the arylpiperazine moiety is a good template for drugs acting on many different biological targets, especially CNS receptors.11-13) As a consequence, many compounds containing this scaffold bind with high affinity at 5-HT 1A receptors, but only a few of them also show high selectivity for 5-HT 1A over other receptors. 14)Structure-activity relationship (SAR) studies, performed with numerous generations of arylpiperazine derivatives, showed that CNS activity and both, receptor affinity and selectivity depend basically on the N-1-aryl substituent and a terminal fragment bound to the N-4 atom of the piperazine moiety by an alkyl chain. In these studies, this alkyl spacer is frequently composed of two to four methylene units. 15,16) On the other hand, the indole substructure is the basic element in a large number of biologically active natural and synthetic products. In fact, until this day, the indole motif is present in more than 400 drugs and 3000 patents.17) The range of applications for these therapeutically relevant compounds includes anti-inflammatory drugs, protein kinase C inhibitors, 5-HT agonists and antagonists, melatonin agonists and glucocorticoid receptor modulators.18) Studies on structural modifications of indolylalkylarylpiperazines carried out by Heinrich et al. 14,19) reported a high-affinity pattern for 5-HT 1A agonism and succeeded in optimizing selectivity over dopamine D 2 receptors. This structural pattern considers a C5-substituted indole ring bearing different functional groups and a parasubstituted arylpiperazine. In these studies, a four-carbon atom chain was employed as a linker of both heterocyclic moieties. On the other hand, a few studies on indolylalkylarylpiperazines containing a propyl chain as a linker have been reported regarding their 5-HT 1B/1D receptor affinity. 20,21) However, the influence of a propylic connecting chain on the affinity of this type ...

Synthesis, Docking, 3-D-Qsar, and Biological Assays of Novel Indole Derivatives Targeting Serotonin Transporter, Dopamine D2 Receptor, and Mao-A Enzyme: In the Pursuit for Potential Multitarget Directed Ligands

“…The synthetic approach for the preparation of the target compounds 7a – o is outlined below. The reaction took place between piperazine benzoxazine derivatives 6 ( a – c ) obtained in a six-step sequence and 82–95% yields ( Scheme 1 ), with 3-indolyl tosylates 1a – c (R = H, F, Br) obtained by reported literature procedures [ 37 , 46 ] to give nine final compounds 7 ( a , b , c , g , h , i , m , n , o ) in a 42–89% yield ( Scheme 2 ).…”

“…Indole derivatives have always been recognized as serotoninergic modulators, given their related structural connection. Furthermore, in our research group, we have extensive experience in the synthesis of indolylpropyl-piperazine derivatives, which have been successfully employed by us [ 33 , 34 , 35 , 36 , 37 ] and other groups [ 38 , 39 ] as very potent serotonin transporter (SERT) ligands. On the other hand, molecular structures containing morpholine [ 40 ] or benzoxazinone [ 41 , 42 , 43 , 44 , 45 ] cores have been reported as MAOi or dopamine D 2 receptor modulators, respectively.…”

Synthesis and Biological Screening of Novel Indolalkyl Arenes Targeting the Serotonine Transporter

“…The novel compounds were synthesized according to Scheme . Compounds 1 ( a and b ) were prepared as previously reported . These compounds 1 ( a and b ) were reacted with p ‐toluenesulfonyl chloride in CH 2 Cl 2 to give tosyl derivatives 2 ( a and b) in 65–82% yield.…”

“…Given our interest in the search of novel indole derivatives with antidepressant properties , we decided to synthesize a new series of indolalkylarenes in order to obtain better affinities in SERT binding. The strategy followed was to connect the indole framework with different heterocyclic moieties using two to three carbon linkers as spacer.…”

4WD to Travel Inside the 5-HT1A Receptor World

“…Such ligands tolerate several substituents in the piperazine ring. Though the optimal linker to connect the indolyl moiety to the N-substituted piperazine is the n-butyl chain, an n-propyl spacer is also suitable, as demonstrated by the good 5-HT 1A R affinity showed by compounds 109 and 110 (Figure 36) [44].…”