N-Hydroxyalkyl Derivatives of 3β-Phenyltropane and 1-Methylspiro[1H-indoline-3,4‘-piperidine]:  Vesamicol Analogues with Affinity for Monoamine Transporters

Abstract

As part of our ongoing structure-activity studies of the vesicular acetylcholine transporter ligand 2-(4-phenylpiperidino)cyclohexanol (vesamicol, 1), 22 N-hydroxy(phenyl)alkyl derivatives of 3 beta-phenyltropane, 6, and 1-methylspiro[1H-indoline-3,4'-piperidine], 7, were synthesized and tested for binding in vitro. Although a few compounds displayed moderately high affinity for the vesicular acetylcholine transporter, no compound was more potent than the prototypical vesicular acetylcholine transporter ligand vesamicol. However, a few derivatives of 6 displayed higher affinity for the dopamine transporter than cocaine. We conclude that modification of the piperidyl fragment of 1 will not lead to more potent vesicular acetylcholine transporter ligands.

Metal‐Catalyzed α‐Arylation of Carbonyl and Related Molecules: Novel Trends in CC Bond Formation by CH Bond Functionalization

“…Freund and Mederski demonstrated the rapid construction of 1,2-dihydro[indole-3,4'-piperidin]-2-ones, [81] which are present in a number of biologically active compounds, for example, neurokinin antagonists, [82] oxytocin antagonists, [83] and monoamine transporter inhibitors. [84] The intramolecular a-arylation of amides was similarly demonstrated by Honda et al in the total syntheses of cherylline and latifine. [85]…”

Metallkatalysierte α‐Arylierungen von Carbonylen und verwandten Molekülen: aktuelle Trends bei der C‐C‐Kupplung über C‐H‐Funktionalisierung

“…Eine Reihe von Beispielen belegt, dass sich die α‐Arylierung von Amiden bei der Totalsynthese biologisch aktiver Verbindungen anwenden lässt. Freund und Mederski zeigten, dass ein rascher Aufbau von 1,2‐Dihydro[indol‐3,4′‐piperidin]‐2‐onen,81 die in einigen biologisch aktiven Verbindungen wie Neurokinin‐Antagonisten,82 Oxytocin‐Antagonisten83 und Monoamin‐Transport‐Inhibitoren84 vorhanden sind, möglich ist. Die intramolekulare α‐Arylierung von Amiden fand auch Anwendung bei den Totalsynthesen von Cheryllin und Latifin (Honda et al.)…”

Piperazine analog of vesamicol: In vitro and in vivo characterization for vesicular acetylcholine transporter

“…The piperidine ring of vesamicol is important structure for high affinity to vesamicol receptor on VAChT (Rogers et al, 1989). Efange et al (1997) reported modification of the piperidine ring, which replaced the piperidine ring with a tropane ring, and did not lead to a more potent affinity for VAChT.…”