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1.  Vesicular monoamine transporter 2: Role as a novel target for drug development 
The AAPS Journal  2006;8(4):E682-E692.
In the central nervous, system, vesicular monoamine transporter 2 (VMAT2) is the only transporter that moves cytoplasmic dopamine (DA) into synaptic vesicles for storage and subsequent exocytotic release. Pharmacologically enhancing DA sequenstration by VMAT2, and thus preventing the oxidation of DA in the cytoplasm, may be a strategy for treating diseases such as Parkinson's disease. VMAT2 may also be a novel target for the development of treatments for psychostimulant abuse. This review summarizes the possible role of VMAT2 as a therapeutic target, VMAT2 ligands reported in the literature, and the structure-activity relationship of these ligands, including tetrabenazine analogs, ketanserin analogs, lobeline analogs, and 3-amine-2-phenylpropene analogs. The molecular structure of VMAT2 and its relevance to ligand binding are briefly discussed.
PMCID: PMC2751365  PMID: 17233532
vesicular monoamine transporter 2; Parkinson's disease; psychostimulant abuse; tetrabenazine; ketanserin; lobeline
2.  N-n-alkylnicotinium analogs, a novel class of antagonists at α4β2* Nicotinic acetylcholine receptors: Inhibition of S(-)-nicotine-evoked 86Rb+Efflux from rat thalamic synaptosomes 
The AAPS Journal  2006;7(4):E922-E930.
PyridineN-n-alkylation of S(-)-nicotine (NIC) affordsN-n-alkylnicotinium analogs, previously shown to competitively inhibit [3H]NIC binding and interact with α4β2* nicotinic receptors (nAChRs). The present study determined the ability of the analogs to inhibit NIC-evoked86Rb+ efflux from rat thalamic synaptosomes to assess functional interaction with α4β2* nAChRs. In a concentration-dependent manner, NIC evoked86Rb+ efflux (EC50=170 nmol/L). Analoginduced inhibition of NIC-evoked86Rb+ efflux varied over a ≈450-fold range. Analogs with longn-alkyl chain lengths (C9−C12) inhibited efflux in the low nmol/L range (IC50=9–20 nmol/L), similar to dihydro-β-erythroidine (IC50=19 nmol/L). Compounds with shortern-alkyl chain lengths (C1−C8) produced inhibition in the low μmol/L range (IC50 =3–12 μmol/L). C10 and C12 analogs completely inhibited NIC-evoked efflux, whereas C1–9 analogs produced maximal inhibition of only 10% to 60%. While the C10 analogN-n-decylnicotiniumiodide (NDNI) did not produce significant inhibition of NIC-evoked dopamine release in previously reported studies, NDNI possesses high affinity for [3H]NIC binding sites (Ki=90 nmol/L) and is a potent and efficacious inhibitor of NIC-evoked86Rb+ efflux as demonstrated in the current studies. Thus, NDNI is a competitive, selective antagonist at α4β2* nAChRs.
PMCID: PMC2750962  PMID: 16594645
nicotine analogs; subtype-selectivity; neuronal nicotinic receptor
3.  A general procedure for the enantioselective synthesis of the minor tobacco alkaloids nornicotine, anabasine, and anatabine 
The AAPS Journal  2005;7(3):E752-E758.
The minor tobacco alkaloids nornicotine, anabasine, and anatabine fromNicotiana tobacum are known to possess nicotinic receptor agonist activity, although they are relatively less potent than S-(−)-nicotine, the principal tobacco alkaloid. Previous pharmacological investigations and structure-activity studies have been limited owing to the lack of availability of the optically pure forms of these minor alkaloids. We now report a 2-step synthetic procedure for the enantioselective synthesis of the optical isomers of nornicotine and anabasine, and a modified procedure for the synthesis of anatabine enantiomers. These procedures involve initial formation of the chiral ketimine resulting from the condensation of either 1R, 2R, 5R-(+)- or 1S, 2S, 5S-(−)-2-hydroxy-3-pinanonewith3-(aminomethyl)pyridine followed by enantioselective C-alkylation with an appropriate halogenoalkane or halogenoalkene species, N-deprotection, and base-catalyzed intramolecular ring closure, to form the appropriate, chirally pure minor tobacco alkaloid. Using this approach, theR-(+)-andS-(−)-enantiomers of the above minor tobacco alkaloids were obtained in good overall chemical yield and excellent enantomeric excess.
PMCID: PMC2751277  PMID: 16353951
Nicotiana alkaloids; tobacco; stereoselective synthesis
4.  Molecular modeling of mono- and bis-quaternary ammonium salts as ligands at the α4β2 nicotinic acetylcholine receptor subtype using nonlinear techniques 
The AAPS Journal  2005;7(3):E678-E685.
The neuronal nicotinic acetylcholine receptor (nAChR) has been a target for drug development studies for over a decade. A series ofmono- andbis-quaternary ammonium salts, known to be antagonists at nAChRs, were separated into 3 structural classes and evaluated using both self-organizing map (SOM) and genetic functional approximation (GFA) algorithm models. Descriptors from these compounds were used to create several nonlinear quantitative structure-activity relationships (QSARs). The SOM methodology was effective in appropriately grouping these compounds with diverse structures and activities. The GFA models were also able to predict the activities of these molecules. Charge distribution and the hydrophobic free energies were found to be important indicators of bioactivity for this particular class of molecules. These QSAR approaches may be a useful to screen and selectin silico new drug candidates from larger compound libraries to be further evaluated in in vitro biological assays.
PMCID: PMC2751270  PMID: 16353944
self-organizing map; genetic functional approximation; neuronal nicotinic acetylcholine receptor
5.  Introduction of unsaturation into theN-n-alkyl chain of the nicotinic receptor antagonists, NONI and NDNI: Effect on affinity and selectivity 
The AAPS Journal  2005;7(1):E201-E217.
N-n-Octylnicotinium iodide (NONI) andN-n-decylnicotinium iodide (NDNI) are selective nicotinic receptor (nAChR) antagonists mediating nicotine-evoked striatal dopamine (DA) release, and inhibiting [3H]nicotine binding, respectively. This study evaluated effects of introducing unsaturation into theN-n-alkyl chains of NONI and NDNI on inhibition of [3H]nicotine and [3H]methyllycaconitine binding (α4β2* and α7* nAChRs, respectively),86Rb+ efflux and [3H]DA release (agonist or antagonist effects at α4β2* and α6β2*-containing nAChRs, respectively). In the NONI series, introduction of a C3-cis-(NONB3c), C3-trans-(NONB3t), C7-double-bond (NONB7e), or C3-triple-bond (NONB3y) afforded a 4-fold to 250-fold increased affinity for [3H]nicotine binding sites compared with NONI. NONB7e and NONB3y inhibited nicotine-evoked86Rb+ efflux, indicating α4β2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotine-evoked [3H]DA overflow compared with NONI (IC50=0.62 μM; Imax=89%), with no change in Imax, except for NONB3y (Imax=50%). In the NDNI series, introduction of a C4-cis-(NDNB4c), C4-trans-double-bond (NDNB4t), or C3-triple-bond (NDNB3y) afforded a 4-fold to 80-fold decreased affinity for [3H]nicotine binding sites compared with NDNI, whereas introduction of a C9-double-bond (NDNB9e) did not alter affinity. NDNB3y and NDNB4t inhibited nicotine-evoked86Rb+ efflux, indicating anatogonism at α4β2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [3H]DA overflow (IC50=0.02–0.14μM, Imax=90%), as did NDNB4c (IC50=0.08 μM; Imax=50%), whereas NDNB3y showed no inhibition. None of the analogs had significant affinity for α7* nAChRs. Thus, unsaturated NONI analogs had enhanced affinity at α4β2*-and α6β2*-containing nAChRs, however a general reduction of affinity at α4β2* and an uncovering of antagonist effects at α6β2*-containing nAChRs were observed with unsaturated NDNI analogs.
PMCID: PMC2751509  PMID: 16146341
Dopamine release; dopamine transporter; drug discovery; nicotinic receptor antagonist; nicotine

Results 1-5 (5)