Benzothiazoles as probes for the 5HT1A receptor and the serotonin transporter (SERT): A search for new dual-acting agents as potential antidepressants

Abstract

The synthesis and evaluation of several benzothiazole based compounds are described in an attempt to identify novel dual-acting 5HT1A receptor and SERT inhibitors as new antidepressants. Binding affinities at the 5HT1A receptor and the serotonin transporter do not appear to be congruent and other areas of the binding sites would need to be explored in order to improve binding simultaneously at both sites. Compounds 20 and 23 show moderate binding affinity at the 5HT1A receptor and the SERT site and thus, have the potential to be further explored as dual-acting agents. In addition, compound 20 binds with low affinity to the dopamine transporter (DAT), the norepinephrine transporter (NET) and 5HT2C receptor, which are desirable properties as selectivity for SERT (and not DAT or NET) is associated with an absence of cardiovascular side-effects.

A comprehensive review in current developments of benzothiazole-based molecules in medicinal chemistry

“…Compounds (234,235) show moderate binding affinity at the 5HT 1A receptor and the SERT site and they have potential to be further explored as dual-acting agents. Also, compound (234) binds with low affinity to the dopamine transporter (DAT), the norepinephrine transporter (NET) and 5HT 2C receptor [272]. The structures for BTA as antidepressant agents are shown in Fig.…”

Identification of a new selective dopamine D4 receptor ligand

“…Compound 17 and 18 are benzothiazole analogs which were previously synthesized and evaluated for binding to the D 2 -like receptors. 15 In this paper, their binding affinities to the D 1 -like receptors were evaluated and the results are reported. The results suggest that a chain length of 4 ( 17 ) produced a more potent agent at the D 4 R than a chain length of 3 ( 18 ).…”

“…15 To obtain the benzo[d]oxazole analogs, 19–22 (Chart 4, Scheme 3), 2-aminophenol was reacted with chloroalkanoyl alkyl halide ( 39 ) to form the amide intermediate ( 40 ) which was then cyclized using polyphosphoric acid (PPA) to obtain 2-(2-chloroalkyl)benzo[d]oxazole, 41 . Compound 41 was used to alkylate 4-chlorophenyl-1-piperazine to yield the desired target compounds 19–22 .…”

“…15 Briefly, 2-aminobenzenethiol ( 46 ) was reacted with 4-chlorobutanoyl chloride ( 47 ) to form 2-(3-chloropropyl)-benzo[d]thiazole, 48 , which was then used to alkylate 2-(piperazin-1-yl)pyrimidine to form the desired target compound, 28 .…”

Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents

“…Antidepressants continue to be the mainstay for treatment of depression [177]. In spite of the availability of wide range of antidepressant agents in the market, major proportion of people doesn't respond to the treatment [178].…”