benzovesamicol and vesamicol

To verify vesamicol as lead structure in the development of radioligands for imaging of VAChT in the brain by PET, we systematically modified this molecule and investigated four different groups of derivatives. Structural changes were conducted in all three ring systems A, B, and C resulting in a library of different vesamicol analogs. Based on their in vitro binding affinity toward VAChT as well as σ1 and σ2 receptors, we performed a structure-affinity relationship (SAR) study regarding both affinity and selectivity. The compounds possessed VAChT affinities in the range of 1.32 nM (benzovesamicol) to >10 μM and selectivity factors from 0.1 to 73 regarding σ1 and σ2 receptors, respectively. We could confirm the exceptional position of benzovesamicols as most affine VAChT ligands. However, we also observed that most of the compounds with high VAChT affinity demonstrated considerable affinity in particular to the σ1 receptor. Finally, none of the various vesamicol analogs in all four groups showed an in vitro binding profile suitable for specific VAChT imaging in the brain.

Topics: Animals; Brain; Dose-Response Relationship, Drug; Female; Molecular Imaging; Molecular Structure; PC12 Cells; Piperidines; Positron-Emission Tomography; Radioligand Assay; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Vesicular Acetylcholine Transport Proteins

To identify selective high-affinity inhibitors of the vesicular acetylcholine transporter (VAChT), we have interposed a carbonyl group between the phenyl and piperidyl groups of the prototypical VAChT ligand vesamicol and its more potent analogues benzovesamicol and 5-aminobenzovesamicol. Of 33 compounds synthesized and tested, 6 display very high affinity for VAChT (K(i), 0.25-0.66 nM) and greater than 500-fold selectivity for VAChT over sigma(1) and sigma(2) receptors. Twelve compounds have high affinity (K(i), 1.0-10 nM) and good selectivity for VAChT. Furthermore, 3 halogenated compounds, namely, trans-3-[4-(4-fluorobenzoyl)piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28b) (K(i) = 2.7 nM, VAChT/sigma selectivity index = 70), trans-3-[4-(5-iodothienylcarbonyl)piperidinyl]-2-hydroxy-1,2,3,4-tetrahydronaphthalene (28h) (K(i) = 0.66 nM, VAChT/sigma selectivity index = 294), and 5-amino-3-[4-(p-fluorobenzoyl)piperidinyl]-2-hydroxy-1,2,3,4,-tetrahydronaphthalene (30b) (K(i) = 2.40 nM, VAChT/sigma selectivity index = 410) display moderate to high selectivity for VAChT. These three compounds can be synthesized with the corresponding radioisotopes so as to serve as PET/SPECT probes for imaging the VAChT in vivo.

Topics: Animals; Drug Discovery; Guinea Pigs; Inhibitory Concentration 50; Piperidines; Rats; Structure-Activity Relationship; Substrate Specificity; Torpedo; Vesicular Acetylcholine Transport Proteins

Located in presynaptic cholinergic nerve terminals, the vesicular acetylcholine transporter (VAChT) represents a potential target for quantitative visualization of early degeneration of cholinergic neurons in Alzheimer's disease using PET. Benzovesamicol derivatives are proposed as radioligands for this purpose. We report QSAR studies of vesamicol and benzovesamicol derivatives taking into account the stereoselectivity of the VAChT binding site. Use of different data sets and different models in this study revealed that both enantiomers of 5-fluoro-3-(4-phenyl-piperidin-1-yl)-1,2,3,4-tetrahydro-naphthalen-2-ol (5-FBVM) are promising candidates, with predicted VAChT affinities between 6.1 and 0.05 nM. The synthesis of enantiopure (R,R)- and (S,S)-5-FBVM and their corresponding triazene precursors for future radiofluorination is reported. Both enantiomers exhibited high in vitro affinity for VAChT [(+)-5-FBVM: K(i)=6.95 nM and (-)-5-FBVM: K(i)=3.68 nM] and were selective for σ(2) receptors (∼70-fold), only (+)-5-FBVM is selective for σ(1) receptors (∼fivefold). These initial results suggest that (+)-(S,S)-5-FBVM warrants further investigation as a potential radioligand for in vivo PET imaging of cholinergic nerve terminals.

Topics: Binding Sites; Ligands; Naphthols; Piperidines; Positron-Emission Tomography; Quantitative Structure-Activity Relationship; Radiopharmaceuticals; Stereoisomerism; Vesicular Acetylcholine Transport Proteins

Vesamicol derivatives are promising candidates as ligands for the vesicular acetylcholine transporter (VAChT) to enable in vivo imaging of cholinergic deficiencies if applied as positron emission tomography radiotracers. So far, optimization of the binding affinity of vesamicol-type ligands was hampered by the lack of respective quantitative structure-activity relationships. We developed the first quantitative model to predict, from molecular structure, the binding affinity of vesamicol-type ligands toward VAChT employing comparative molecular field analysis (CoMFA) for a set of 37 ligands, covering three different structural types (4-phenylpiperidine, spiro, and tropan derivatives of vesamicol). The prediction capability was assessed by leave-one-out cross-validation (LOO) and through leaving out and predicting 50% of the compounds selected such that both the training and the prediction sets cover almost the whole range of experimental data. The statistics indicate a significant prediction power of the models ( q (2) (LOO) = 0.66, q (2) (50% out) = 0.59-0.74). The discussion includes detailed analyses of CoMFA regions critical for ligand-VAChT binding, identifying structural implications for high binding affinity.

Topics: Binding Sites; Fluorobenzenes; Iodobenzenes; Ligands; Models, Molecular; Molecular Structure; Piperidines; Quantitative Structure-Activity Relationship; Reproducibility of Results; Static Electricity; Stereoisomerism; Vesicular Acetylcholine Transport Proteins

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.

Topics: Anesthetics, Local; Animals; Carrier Proteins; Cocaine; Dopamine Plasma Membrane Transport Proteins; Guinea Pigs; Kinetics; Male; Membrane Glycoproteins; Membrane Transport Proteins; Molecular Conformation; Nerve Tissue Proteins; Neuromuscular Depolarizing Agents; Neurotransmitter Agents; Piperidines; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Tropanes; Vesicular Acetylcholine Transport Proteins; Vesicular Transport Proteins

In an effort to develop selective inhibitors of vesicular acetylcholine storage, we have synthesized a series of semirigid vesamicol receptor ligands based on the structure of 2-(4-phenylpiperidino)-cyclohexanol (vesamicol, AH5183, 1). In these compounds, the planes of the phenyl and piperidyl moieties of the parent ligand 1 are held at right angles by vinyl, ethylene, and propylene bridges to form N-substituted derivatives of spiro[indene-1,4'-piperidine], 2,3-dihydrospiro[indene-1,4'-piperidine], and 3,4-dihydrospiro[naphthalene-1(2H),4'-piperidine], respectively. Preliminary evaluation of these compounds in electric organ synaptic vesicles revealed several potent vesamicol receptor ligands, such as 1'-(2-hydroxy-1,2,3,4-tetrahydronaphth-3-yl)spiro[1H-indene-1,4'-p iperidine (11b) and 1'-(2-hydroxy-1,2,3,4-tetrahydronaphth-3-yl)spiro[2-bromo-1H-in den e- 1,4'-piperidine] (14), which display subnanomolar affinity for this receptor. In general, the vinyl and ethylene bridges yielded the most potent analogs while the propylene-bridged analogs were among the least potent compounds. The increased rigidity of these spiro-fused compounds, relative to the corresponding simple 4-phenylpiperidine derivatives of vesamicol, is expected to confer greater selectivity for the vesamicol receptor.

Topics: Acetylcholine; Alkenes; Animals; Electric Organ; Ethylenes; Indenes; Molecular Conformation; Molecular Structure; Neuromuscular Depolarizing Agents; Piperidines; Receptors, Cholinergic; Structure-Activity Relationship; Synaptic Vesicles; Vinyl Compounds