Systematic in Vivo Screening of a Series of 1-Propyl-4-arylpiperidines against Dopaminergic and Serotonergic Properties in Rat Brain: A Scaffold-Jumping Approach

Abstract

A series of 1-propyl-4-arylpiperidines were synthesized and their effects on the dopaminergic and serotonergic systems tested in vivo and in vitro. Scaffold jumping among five- and six-membered bicyclic aryl rings attached to the piperidine ring had a marked impact on these effects. Potent and selective dopamine D(2) receptor antagonists were generated from 3-indoles, 3-benzoisoxazoles, 3-benzimidazol-2-one, and 3-benzothiophenes. In contrast, 3-benzofuran was a potent and selective inhibitor of monoamine oxidase (MAO) A. The effects of the synthesized compounds on 3,4-dihydroxyphenylacetic acid (DOPAC) levels correlated very well with their affinity for dopamine D(2) receptors and MAO A. In the 4-arylpiperidine series, the most promising compound for development was the 6-chloro-3-(1-propyl-4-piperidyl)-1H-benzimidazol-2-one (19), which displayed typical dopamine D(2) receptor antagonist properties in vivo but produced only a partial reduction on spontaneous locomotor activity. This indicates that the compound may have a lower propensity to induce parkinsonism in patients.

Structure-guided discovery of a luminescent theranostic toolkit for living cancer cells and the imaging behavior effect

“…in living cells. [53][54][55][56] Moreover, previous studies have suggested that methoxy group played a key role in the interaction between several FDA-approved EGFR inhibitors (e.g. erlotinib, getinib, brigatinib and osimertinib) and EGFR.…”

Design, Synthesis and Biological Evaluation of Potent Antioxidant 1‐(2,5‐Dimethoxybenzyl)‐4‐arylpiperazines and N‐Azolyl Substituted 2‐(4‐Arylpiperazin‐1‐yl)

“…Piperazine is a privileged heterocyclic ring system present in a number of therapeutic agents with diverse pharmacological activities . In particular, N ‐arylpiperazines are found in a wide variety of small molecules binding to a diverse range of therapeutically relevant protein targets from enzymes, such as monoamine oxidase A (MAO−A) and B (MAO−B), to G protein‐coupled receptors (GPCRs), such as dopamine and serotonin receptors …”

Nitrimines as Reagents for Metal‐Free Formal C(sp2)–C(sp2) Cross‐Coupling Reactions

“…Indole-, pyrrole-, and coumarin-containing therapeutic agents served as the inspiration for our studies. For example, RU24969, [14] phenprocoumon, and tipranavir are attractive medicinal targets which may benefit from nitrimine cross-coupling chemistry (Figure 1). With these targets in mind, the scope of reactions between various nitrimine electrophiles and coupling partners was explored.…”