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

• Published in: European journal of medicinal chemistry Vol. 53; pp. 124 - 132
• Main Authors: Zhu, Xue Y., Etukala, Jagan R., Eyunni, Suresh V.K., Setola, Vincent, Roth, Bryan L., Ablordeppey, Seth Y.
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier Masson SAS 01-07-2012; Elsevier
• Subjects: 5HT1A agents; 5HT1A binding; Antidepressive Agents - chemical synthesis; Antidepressive Agents - chemistry; Antidepressive Agents - metabolism; Antidepressive Agents - pharmacology; Benzothiazoles; Benzothiazoles - chemical synthesis; Benzothiazoles - chemistry; Benzothiazoles - metabolism; Benzothiazoles - pharmacology; Biological and medical sciences; Drug Design; Dual-acting antidepressants; Medical sciences; Miscellaneous; Pharmacology. Drug treatments; Potential SERT inhibitors; Receptor, Serotonin, 5-HT1A - metabolism; Serotonin Plasma Membrane Transport Proteins - metabolism; SERT inhibition; Structure-Activity Relationship; Substrate Specificity; Dual-acting antidepressants; Potential SERT inhibitors; 5HT1A binding; 5HT1A agents; SERT inhibition; Benzothiazoles; 5HT; binding; agents
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2012.03.042

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.
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► Four old and 17 new benzothiazoles have been synthesized. ► Several have been identified as leads of dual-acting agents at 5HT1A and SERT sites. ► One agent has little or no binding to receptors implicated in known side effects of SSRIs.