Novel Pyridylmethylamines as Highly Selective 5-HT_1A Superagonists

Abstract

To further improve the maximal serotonergic efficacy and better understand the configurational requirements for 5-HT(1A) binding and activation, we generated and biologically investigated structural variants of the lead structure befiradol. For a bioisosteric replacement of the 3-chloro-4-fluoro moiety, a focused library of 63 compounds by solution phase parallel synthesis was developed. Target binding of our compound collection was investigated, and their affinities for 5-HT(2), α(1), and α(2)-adrenergic as well as D(1)-D(4) dopamine receptors were compared. For particularly interesting test compounds, intrinsic activities at 5-HT(1A) were examined in vitro employing a GTPγS assay. The investigation guided us to highly selective 5HT(1A) superagonists. The benzothiophene-3-carboxamide 8bt revealed almost exclusive 5HT(1A) recognition with a K(i) value of 2.7 nM and a maximal efficacy of 124%. To get insights into the bioactive conformation of our compound collection, we synthesized conformationally constrained bicyclic scaffolds when SAR data indicated a chair-type geometry and an equatorially dispositioned aminomethyl substituent for the 4,4-disubstituted piperidine moiety.

Radiosynthesis and Preclinical Evaluation of 18F-F13714 as a Fluorinated 5-HT1A Receptor Agonist Radioligand for PET Neuroimaging

“…Third and importantly, F13714 exhibits an exceptionally high affinity for 5-HT 1A receptors, with a Ki of 0.1 nM or lessthat is, 0.06 nM at rat cortical 5-HT 1A receptors, 0.10 nM at rat hippocampal 5-HT 1A receptors, and 0.04 nM at recombinant human 5-HT 1A receptors expressed in Chinese hamster ovary cells (30)(31)(32). Its remarkable agonist efficacy leads some authors to consider agonists from this chemical series as superagonists (33). The high affinity of F13714 is crucial because the specific binding of a radiotracer is a function of its affinity for the site relative to the density (Bmax) of that binding site.…”

Computer-Aided Drug Design Approaches to Study Key Therapeutic Targets in Alzheimer’s Disease

“…Curiously, a synergystic effect on the decrease of abnormal involuntary movements was observed when 5-HT 1B R agonists were co-administered with 5-HT 1A R agonists [202]. Overall, targeting 5-HT 1A Rs [203][204][205][206][207] and 5-HT 1B Rs [208][209][210][211] with agonists may provide potential benefits on the reversal of PD symptoms.…”

4WD to Travel Inside the 5-HT1A Receptor World

“…In 2013, 17 was marketed by Neurolixis with indication for the treatment of L-DOPA-induced dyskinesia in Parkinson's disease [19]. The 3-chloro-4-fluorophenyl moiety of 17 can be bioisosterically replaced by both unsaturated and saturated lipophilic moieties [20]. Among the investigated compounds, the highly selective 5-HT 1A R superagonist benzothiophene-3-carboxamide 18 almost exclusively recognizes Finally, the presence of a 3β-aminotropane moiety instead of the piperazine or piperidine ring is unfavorable for the development of High affinity 5-HT 1A R ligands (Figure 14) [22].…”