Linked Life Data

16107155

Source:http://linkedlifedata.com/resource/pubmed/id/16107155

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
17
pubmed:dateCreated
2005-8-18
pubmed:abstractText
(-)-Lobeline (2R,6S,10S), an antagonist at nicotinic acetylcholine receptors (nAChRs), inhibits the neurochemical and behavioral effects of methamphetamine and inhibits dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. VMAT2 is a target for the development of treatments for methamphetamine abuse. Structural modification of lobeline affords the defunctionalized analogues meso-transdiene (MTD) and lobelane, which have high potency and selectivity for VMAT2. To establish the structure-activity relationships within this novel class of VMAT2 ligands, specific stereochemical forms of MTD, lobelane, and other structurally related analogues have been synthesized. These compounds have been evaluated for inhibition of [(3)H]nicotine ([(3)H]NIC) binding (alpha4beta2 nAChR), [(3)H]methyllycaconitine ([(3)H]MLA) binding (alpha7 nAChR), and [(3)H]dihydrotetrabenazine ([(3)H]DTBZ) binding (VMAT2). Generally, all of these analogues had lower affinities at alpha4beta2 and alpha7 nAChRs compared to lobeline, thereby increasing selectivity for VMAT2. The following structural modifications resulted in only modest changes in affinity for VMAT2, affording analogues that were less potent than the lead compound, lobelane: (1) altering the stereochemistry at the C-2 and C-6 positions of the piperidino ring, (2) varying unsaturation in the piperidino C-2 and C-6 substituents, (3) introducing unsaturation into the piperidine ring, (4) ring-opening or eliminating the piperidine ring, and (5) removing the piperidino N-methyl group. Furthermore, incorporating a quaternary ammonium group into defunctionalized lobeline molecules in the cis-series resulted in significant loss of affinity for VMAT2, whereas only a modest change in affinity was obtained in the trans-series. The most potent (K(i) = 630 nM) and VMAT2-selective compound evaluated was the N-methyl-2,6-cis-bis(naphthaleneethyl)piperidine analogue (1-NAP-lobelane), in which the phenyl groups of lobelane were replaced with 1-naphthyl moieties. Thus, initial structure-activity relationship studies reveal that the most promising structural changes to the lobeline molecule that lead to enhancement of VMAT2 affinity and selectivity are defunctionalization, affording lobelane and MTD, and replacement of the phenyl rings of lobelane with other aromatic moieties that have a pi-extended structure.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
0022-2623
pubmed:author
pubmed:issnType
Print
pubmed:day
25
pubmed:volume
48
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
5551-60
pubmed:dateRevised
2007-11-14
pubmed:meshHeading
pubmed:year
2005
pubmed:articleTitle
Defunctionalized lobeline analogues: structure-activity of novel ligands for the vesicular monoamine transporter.
pubmed:affiliation
College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536-0082, USA.
pubmed:publicationType
Journal Article, In Vitro, Research Support, U.S. Gov't, P.H.S., Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural