PubMed Health⌕ Search

Biomedical subjects

Peter A Crooks

Publications and source records attributed to Peter A Crooks.

At least 19 recordsLinked to original sources
PubMed2007

Nornicotine inhibition of dopamine transporter function in striatum via nicotinic receptor activation.

Nornicotine, a tobacco alkaloid and N-demethylated nicotine metabolite, releases DA from superfused rat striatal slices in a mecamylamine-sensitive manner, indicating nicotinic receptor (nAChR) modulation of this response. The current study determined the effect of nornicotine on rat striatal dopamine transporter (DAT) function using in vivo voltammetry. In a dose-related and mecamylamine-sensitive manner, nornicotine (0.35-12.0 mg/kg, s.c.) decreased DA clearance, suggesting that nornicotine inhibits striatal DAT function via a nAChR-mediated mechanism. Furthermore, the nAChRs mediating the nornicotine-induced inhibition of DAT function appear to be different from those activated by nicotine which increases DA clearance. Understanding the actions of nornicotine in brain may have significance for emerging therapeutics and for the management of nicotine dependence.

Acetylcholine↗
PubMed2006

Modeling subtype-selective agonists binding with alpha4beta2 and alpha7 nicotinic acetylcholine receptors: effects of local binding and long-range electrostatic interactions.

The subtype-selective binding of 14 representative agonists with alpha4beta2 and alpha7 nicotinic acetylcholine receptors (nAChRs) has been studied by performing homology modeling, molecular docking, geometry optimizations, and microscopic and phenomenological binding free energy calculations. All of the computational results demonstrate that the subtype selectivity of the agonists binding with alpha4beta2 and alpha7 7 nAChRs is affected by both local binding and long-range electrostatic interactions between the receptors and the protonated structures of the agonists. The effects of the long-range electrostatic interactions are mainly due to the distinct difference in the net charge of the ligand-binding domain between the two nAChR subtypes. For the alpha4beta2-selective agonists examined, the microscopic binding modes with the alpha4beta2 nAChR are very similar to the corresponding modes with the alpha7 nAChR, and therefore, the subtype selectivity of these agonists binding with alpha4beta2 and alpha7 nAChRs is dominated by the long-range electrostatic interactions. For the alpha7-selective agonists, their microscopic binding modes with the alpha7 nAChR are remarkably different from those with the alpha4beta2 nAChR so that the local binding (including the hydrogen bonding and cation-pi interactions) with the alpha7 nAChR is much stronger than that with the alpha4beta2 nAChR. The calculated phenomenological binding free energies are in good agreement with available experimental data for the relative binding free energies concerning the subtype selectivity of agonists binding with the two different nAChR subtypes. The fundamental insights obtained in the present study should be valuable for future rational design of potential therapeutic agents targeted to specific nAChR subtypes.

Amino Acid Sequence↗
PubMed2006

Vesicular monoamine transporter 2: role as a novel target for drug development.

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 sequestration 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.

Animals↗
PubMed2006

The effects of a novel nicotinic receptor antagonist N,N-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB) on acute and repeated nicotine-induced increases in extracellular dopamine in rat nucleus accumbens.

The present study examined the effects of the novel nicotinic acetylcholine receptor (nAChR) antagonist, N,N'-dodecane-1,12-diyl-bis-3-picolinium dibromide (bPiDDB), after acute and repeated nicotine treatment on extracellular dopamine (DA) levels in rat nucleus accumbens (NAcc), using in vivo microdialysis. Acute nicotine (0.4mg/kg, sc) injection produced an increase (232% of basal) in extracellular DA, which was attenuated by pretreatment with the nAChR antagonist mecamylamine (4mg/kg, sc). Pretreatment with bPiDDB (1 or 3mg/kg, sc) dose-dependently reduced the increase in extracellular DA produced by nicotine (0.4mg/kg, sc), but not by amphetamine (0.5mg/kg, sc). Basal levels of NAcc DA increased in animals that had been pretreated with nicotine (0.4mg/kg, sc) for 5 days compared to saline. In addition, nicotine challenge further increased extracellular DA (237% of basal). The increase in DA in NAcc following repeated nicotine was blocked by pretreatment with mecamylamine (4mg/kg, sc) and bPiDDB (1 or 3mg/kg, sc). These results indicate that bPiDDB likely acts as an antagonist at neuronal nAChRs to inhibit DA release in NAcc after acute or repeated nicotine administration. The ability of bPiDDB to inhibit the effect of nicotine in NAcc, combined with previous studies showing decreased nicotine self-administration in rats provides support for bPiDDB as a potential lead compound for the development of a novel pharmacotherapy for nicotine dependence.

Amphetamine↗
PubMed2006

Des-keto lobeline analogs with increased potency and selectivity at dopamine and serotonin transporters.

A series of des-keto lobeline analogs has been synthesized and evaluated for their ability to inhibit the dopamine transporter (DAT) and serotonin transporter (SERT) function and for their affinity for the synaptic vesicle monoamine transporter (VMAT2), as well as for alpha4beta2( *) and alpha7( *) neuronal nicotinic acetylcholine receptors (nAChRs). The enantiomers 8R-hydroxylobel-9-ene (3a) and 10S-hydroxylobel-7-ene (3c) exhibited high potency and selectivity at SERT and DAT, respectively.

Dopamine Plasma Membrane Transport Proteins↗
PubMed2006

Synthesis and hydrolytic behavior of two novel tripartate codrugs of naltrexone and 6beta-naltrexol with hydroxybupropion as potential alcohol abuse and smoking cessation agents.

A codrug approach for simultaneous treatment of alcohol abuse and tobacco dependence is considered as very desirable because of substantial evidence that smoking is increased significantly during drinking, and that smoking is regarded as a behavioral 'cue' for the urge to consume alcohol. The purpose of this study was to design and synthesize codrugs for simultaneous treatment of alcohol abuse and tobacco dependence. Two novel tripartate codrugs of naltrexone (NTX) and naltrexol (NTXOL) covalently linked to hydroxybupropion (BUPOH) were synthesized (25 and 26, respectively), and their hydrolytic cleavage to the parent drugs was determined. These codrugs were generally less crystalline when compared to NTX, or NTXOL, as indicated by their lower melting points, and were expected to be more lipid-soluble. Also, the calculated clogP values were found to be higher for the codrugs compared to those for NTX and NTXOL. The studies on the hydrolysis of the codrugs provided good evidence that they could be efficiently converted to the parent drugs in buffer at physiological pH. Thus, these codrugs are likely to be cleaved enzymatically in vivo to generate the parent drugs, and are considered to be potential candidates for simultaneous treatment of alcohol abuse and tobacco dependence.

Alcohol Deterrents↗
PubMed2006

Opiate receptor binding properties of morphine-, dihydromorphine-, and codeine 6-O-sulfate ester congeners.

A series of 3-O-acyl-6-O-sulfate esters of morphine, dihydromorphine, N-methylmorphinium iodide, codeine, and dihydrocodeine were prepared and evaluated for their ability to bind to mu-, delta-, kappa(1)-, kappa(2)-, and kappa(3)-opiate receptors. Several compounds exhibited good affinity for the mu-opiate receptor. Morphine-3-O-propionyl-6-O-sulfate had four times greater affinity than morphine at the mu-opiate receptor and was the most selective compound at this receptor subtype.

Animals↗
PubMed2006

Enhancement of transdermal delivery of 6-beta-naltrexol via a codrug linked to hydroxybupropion.

Naltrexone (NTX) is a potent opioid antagonist used in the treatment of alcohol dependence and heroin abuse. Compared with naloxone, NTX has a longer duration of action largely attributed to its major active metabolite, 6-beta-naltrexol. The purpose of this study was to increase the delivery of 6-beta-naltrexol across human skin in vitro via a novel codrug. A carbonate codrug of 6-beta-naltrexol linked to hydroxybupropion was synthesized and evaluated. In vitro human skin permeation rates were measured using a flow-through diffusion cell system. The drug melting points, solubilities, chemical stability, and skin disposition were determined. The carbonate codrug was hydrolyzed on passing through skin and appeared as a combination of intact codrug and parent drugs, 6-beta-naltrexol and hydroxybupropion, in the receiver solution. The codrug provided a significantly (p<0.05) higher 6-beta-naltrexol flux across human skin than 6-beta-naltrexol base. The extent of parent drug regeneration in the skin ranged from 56 to 86%. A higher stratum corneum partition coefficient and rapid bioconversion of the carbonate codrug in the skin correlated with increased 6-beta-naltrexol delivery rates.

Administration, Cutaneous↗
PubMed2006

Effect of pH on sublingual absorption of oxycodone hydrochloride.

The purpose of this study was to develop a sublingual spray drug delivery formulation of oxycodone and evaluate the effect of formulation pH on sublingual absorption of oxycodone for acute pain management using rabbit as the animal model. Using a new, sensitive, and specific liquid chromatography/mass spectrometry (LC/MS) with electrospray ionization detector assay, the absorption bioavailability of sublingual oxycodone was determined in rabbits by comparing plasma concentration after sublingual spray delivery with equivalent intravenous dose. The effect of formulation pH on sublingual absorption of oxycodone was also tested on rabbits that had received oxycodone sublingually at a dose of 0.1 mg/0.1 mL (pH 4.0 and 9.0). Blood samples were collected at different time points, and plasma oxycodone concentrations were determined by LC/MS. Following administration of a 0.1 mg dose, the average C(max) values were found to be 64.9 +/- 12.1 and 95.2 +/- 10.1 ng/mL, for pH 4.0 and 9.0, respectively. The area under the curve (AUC) values were found to be 5807.0, and 8965.3 ng.min/mL for formulation pH 4.0 and 9.0, respectively. The mean sublingual bioavailability of oxycodone was 45.4% +/- 20.1% and 70.1% +/- 17.9%, for pH 4.0 and 9.0, respectively. The formulation pH had no significant influence on oxycodone bioavailability (P < .05). A sublingual spray dosage form of oxycodone hydrochloride would be a good alternative for fast onset pain management, especially in children.

Absorption↗
PubMed2006

1-(1H-Indol-3-ylcarbonyl)-N-(4-methoxybenzyl)formamide.

In the title compound, C18H16N2O3, the indole ring is planar and the two adjacent carbonyl groups are mutually trans oriented with a torsion angle of 144.8 (3) degrees. The single C-C bond linking the two carbonyl functionalities is 1.539 (4) A. Molecules are linked into a two-dimensional network by intermolecular N-H...O hydrogen bonds.

Benzyl Compounds↗
PubMed2006

Synthesis and stability of two indomethacin prodrugs.

The purpose of this study was to synthesize and study the in vitro enzymatic and non-enzymatic hydrolysis of indomethacin-TEG ester and amide prodrugs. It was found that the ester conjugate 10 was comparatively stable between pH 3 and 6 (half-life>90h), with a half-life equal to 5.2h in 80% buffered plasma. In contrast, the amide conjugate 12 appeared to be stable over the entire pH range studied with the only observed degradation being cleavage of the indolic N-4-chlorobenzoyl moiety.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2006

QSAR modeling of mono- and bis-quaternary ammonium salts that act as antagonists at neuronal nicotinic acetylcholine receptors mediating dopamine release.

Back-propagation artificial neural networks (ANNs) were trained on a dataset of 42 molecules with quantitative IC50 values to model structure-activity relationships of mono- and bis-quaternary ammonium salts as antagonists at neuronal nicotinic acetylcholine receptors (nAChR) mediating nicotine-evoked dopamine release. The ANN QSAR models produced a reasonable level of correlation between experimental and calculated log(1/IC50) (r2=0.76, r(cv)2=0.64). An external test for the models was performed on a dataset of 18 molecules with IC50 values >1 microM. Fourteen of these were correctly classified. Classification ability of various models, including self-organizing maps (SOM), for all 60 molecules was also evaluated. A detailed analysis of the modeling results revealed the following relative contributions of the used descriptors to the trained ANN QSAR model: approximately 44.0% from the length of the N-alkyl chain attached to the quaternary ammonium head group, approximately 20.0% from Moriguchi octanol-water partition coefficient of the molecule, approximately 13.0% from molecular surface area, approximately 12.6% from the first component shape directional WHIM index/unweighted, approximately 7.8% from Ghose-Crippen molar refractivity, and 2.6% from the lowest unoccupied molecular orbital energy. The ANN QSAR models were also evaluated using a set of 13 newly synthesized compounds (11 biologically active antagonists and two biologically inactive compounds) whose structures had not been previously utilized in the training set. Twelve among 13 compounds were predicted to be active which further supports the robustness of the trained models. Other insights from modeling include a structural modification in the bis-quinolinium series that involved replacing the 5 and/or 8 as well as the 5' and/or 8' carbon atoms with nitrogen atoms, predicting inactive compounds. Such data can be effectively used to reduce synthetic and in vitro screening activities by eliminating compounds of predicted low activity from the pool of candidate molecules for synthesis. The application of the ANN QSAR model has led to the successful discovery of six new compounds in this study with experimental IC50 values of less than 0.1 microM at nAChR subtypes responsible for mediating nicotine-evoked dopamine release, demonstrating that the ANN QSAR model is a valuable aid to drug discovery.

Dopamine↗
PubMed2006

N-n-alkylnicotinium analogs, a novel class of antagonists at alpha 4 beta 2* nicotinic acetylcholine receptors: inhibition of S(-)-nicotine-evoked 86Rb+ efflux from rat thalamic synaptosomes.

Pyridine N-n-alkylation of S(-)-nicotine (NIC) affords N-n-alkylnicotinium analogs, previously shown to competitively inhibit [(3)H]NIC binding and interact with alpha4beta2* nicotinic receptors (nAChRs). The present study determined the ability of the analogs to inhibit NIC-evoked (86)Rb(+) efflux from rat thalamic synaptosomes to assess functional interaction with alpha4beta2* nAChRs. In a concentration-dependent manner, NIC evoked (86)Rb(+) efflux (EC(50) = 170 nmol/L). Analog-induced inhibition of NIC-evoked (86)Rb(+) efflux varied over a approximately 450-fold range. Analogs with long n-alkyl chain lengths (C(9)-C(12)) inhibited efflux in the low nmol/L range (IC(50) = 9-20 nmol/L), similar to dihydro-beta-erythroidine (IC(50) = 19 nmol/L). Compounds with shorter n-alkyl chain lengths (C(1)-C(8)) produced inhibition in the low micromol/L range (IC(50) = 3-12 micromol/L). C(10) and C(12) analogs completely inhibited NIC-evoked efflux, whereas C(1-9) analogs produced maximal inhibition of only 10% to 60%. While the C(10) analog N-n-decylnicotinium iodide (NDNI) did not produce significant inhibition of NIC-evoked dopamine release in previously reported studies, NDNI possesses high affinity for [(3)H]NIC binding sites (K(i) = 90 nmol/L) and is a potent and efficacious inhibitor of NIC-evoked (86)Rb(+) efflux as demonstrated in the current studies. Thus, NDNI is a competitive, selective antagonist at alpha4beta2* nAChRs.

Animals↗
PubMed2005

A general procedure for the enantioselective synthesis of the minor tobacco alkaloids nornicotine, anabasine, and anatabine.

The minor tobacco alkaloids nornicotine, anabasine, and anatabine from Nicotiana 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-pinanone with 3-(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, the R-(+)- and S-(-)-enantiomers of the above minor tobacco alkaloids were obtained in good overall chemical yield and excellent enantomeric excess.

Alkaloids↗
PubMed2005

Molecular modeling of mono- and bis-quaternary ammonium salts as ligands at the alpha4beta2 nicotinic acetylcholine receptor subtype using nonlinear techniques.

The neuronal nicotinic acetylcholine receptor (nAChR) has been a target for drug development studies for over a decade. A series of mono- and bis-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 select in silico new drug candidates from larger compound libraries to be further evaluated in in vitro biological assays.

Ligands↗
PubMed2005

(Z)-2-(3-methoxybenzylidene)-1-azabicyclo[2.2.2]octan-3-one.

The crystal structure of the title compound, C(15)H(17)NO(2), contains two nearly identical but crystallographically independent molecules, each with a double bond connecting an azabicyclic ring system to a 3-methoxybenzylidene moiety. The space group is triclinic P-1. The benzene ring is twisted by 18.44 (5) and 22.35 (4) degrees with respect to the plane of the double bond connected to the azabicyclic ring system for the two molecules. In addition to C-H...pi interactions, molecules are held together in the solid state by van der Waals interactions.

Crystallization↗
PubMed2005

Modeling multiple species of nicotine and deschloroepibatidine interacting with alpha4beta2 nicotinic acetylcholine receptor: from microscopic binding to phenomenological binding affinity.

A variety of molecular modeling, molecular docking, and first-principles electronic structure calculations were performed to study how the alpha4beta2 nicotinic acetylcholine receptor (nAChR) binds with different species of two typical agonists, (S)-(-)-nicotine and (R)-(-)-deschloroepibatidine, each of which is distinguished by different free bases and protonation states. On the basis of these results, predictions were made regarding the corresponding microscopic binding free energies. Hydrogen-bonding and cation-pi interactions between the receptor and the respective ligands were found to be the dominant factors differentiating the binding strengths of different microscopic binding species. The calculated results and analyses demonstrate that, for each agonist, all the species are interchangeable and can quickly achieve a thermodynamic equilibrium in solution and at the nAChR binding site. This allows quantitation of the equilibrium concentration distributions of the free ligand species and the corresponding microscopic ligand-receptor binding species, their pH dependence, and their contributions to the phenomenological binding affinity. The predicted equilibrium concentration distributions, pK(a) values, absolute phenomenological binding affinities, and their pH dependence are all in good agreement with available experimental data, suggesting that the computational strategy from the microscopic binding species and affinities to the phenomenological binding affinity is reliable for studying alpha4beta2 nAChR-ligand binding. This should provide valuable information for future rational design of drugs targeting nAChRs. The general strategy of the "from-microscopic-to-phenomenological" approach for studying interactions of alpha4beta2 nAChRs with (S)-(-)-nicotine and (R)-(-)-deschloroepibatidine may also be useful in studying other types of ligand-protein interactions involving multiple molecular species of a ligand and in associated rational drug design.

Binding Sites↗