Synthesis and evaluation of a series of homologues of lobelane at the vesicular monoamine transporter-2.
A series of lobelane homologues has been synthesized and evaluated for their [(3)H]DTBZ binding affinity at the vesicular monoamine transporter-2 (VMAT2). The structure-activity relationships (SAR) indicate that for retention of binding affinity at VMAT2, the lengths of the methylene linkers should be no shorter than one methylene unit at C-6 of the piperidine ring, and no shorter than two methylene units at C-2 of the piperidine ring. These results indicate that the intramolecular distances between the piperidine ring and two phenyl rings in lobelane analogues are an important criterion for retention of high affinity at VMAT2.
Zheng
Guangrong
G
Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Rose Street, Lexington, KY 40536-0082, USA.
Dwoskin
Linda P
LP
Deaciuc
Agripina G
AG
Crooks
Peter A
PA
D000818:Animals; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008120:Lobeline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D008956:Models, Chemical; D010100:Oxygen / Q000737:chemistry; D010880:Piperidines / Q000737:chemistry; D051381:Rats; D013329:Structure-Activity Relationship; D050492:Vesicular Biogenic Amine Transport Proteins / Q000378:metabolism; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism*
D010880:Piperidines; D050492:Vesicular Biogenic Amine Transport Proteins; D050493:Vesicular Monoamine Transport Proteins; C540157:lobelane; C032727:piperidine; D008120:Lobeline; D010100:Oxygen