Structure–Activity Relationships and Therapeutic Potentials of 5-HT₇ Receptor Ligands: An Update

Abstract

Serotonin 5-HT receptor (5-HTR) has been the subject of intense research efforts because of its presence in brain areas such as the hippocampus, hypothalamus, and cortex. Preclinical data link the 5-HTR to a variety of central nervous system processes including the regulation of circadian rhythms, mood, cognition, pain processing, and mechanisms of addiction. 5-HTR blockade has antidepressant effects and may ameliorate cognitive deficits associated with schizophrenia. 5-HTR has been recently shown to modulate neuronal morphology, excitability, and plasticity, thus contributing to shape brain networks during development and to remodel neuronal wiring in the mature brain. Therefore, the activation of 5-HTR has been proposed as a therapeutic approach for neurodevelopmental and neuropsychiatric disorders associated with abnormal neuronal connectivity. This Perspective celebrates the silver jubilee of the discovery of 5-HTR by providing a survey of recent studies on the medicinal chemistry of 5-HTR ligands and on the neuropharmacology of 5-HTR.

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists

“…AZ-853 and AZ-861 are chemical analogs that differ only in the quality of the fluorine substituent in the phenyl ring attached to piperazine. A small change in the chemical structure may cause differences not only in chemical and physical properties but also in pharmacological and pharmacokinetic characteristics (e.g., paliperidone vs. risperidone) [17][18][19][20]. Our previous investigations revealed that compounds AZ-853 and AZ-861 possess high affinity for serotonergic 5-HT 1A R and are 5-HT 1A R antagonists in CHO-K1 cells in the Ca 2+ mobilization assay, with AZ-861 showing 2-fold higher K b value [8].…”

Serotonin Receptors for Treatment of Insomnia

“…In addition, clinical evaluation has shown that JNJ-18038683 significantly increased the time of REM sleep episode compared to placebo and reduced total REM sleep time. These data demonstrated that the effect of 5-HT 7 receptor blockade induced by JNJ-18038683 on REM sleep is translated from rodents to humans [26,57]. JNJ-18038683 is now undergoing a phase II clinical trials as adjunctive treatment to improve cognition impairment and to alleviate depressive symptoms in stable bipolar patients [57].…”

“…These data demonstrated that the effect of 5-HT 7 receptor blockade induced by JNJ-18038683 on REM sleep is translated from rodents to humans [26,57]. JNJ-18038683 is now undergoing a phase II clinical trials as adjunctive treatment to improve cognition impairment and to alleviate depressive symptoms in stable bipolar patients [57]. Kim et al [27] have discovered Azepine…”

Prior Activation of 5-HT7 Receptors Modulates the Conditioned Place Preference With Methylphenidate

“…TP-22 exhibited 5-HT7R agonist properties (Table 1) and improved in vitro metabolic stability as compared to LP-211 (half-life = 45 min and 15 min, respectively; Lacivita et al, 2016). TP-22 was able to stimulate neurite outgrowth in neuronal primary cultures in shorter time and at a lower concentration than LP-211, showing a comparable in vivo bio-distribution profile (brain C max 515 ng/mL and 540 ng/mL, respectively; Lacivita et al, 2016; Modica et al, 2018). Starting from the evidence that the administration of methylphenidate (MPH) causes an upregulation of 5-HT7Rs (Adriani et al, 2006; Leo et al, 2009), and in light of the several findings that propose a physiological role for 5-HT in reward guided behavior (Broderick and Phelix, 1997; Luo et al, 2016; Fischer and Ullsperger, 2017), we formulated the hypothesis that a previous administration of a 5-HT7 agonist could have modulatory effects on the well-known rewarding and stimulant MPH effects.…”