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Biomedical subjects

Peter A Crooks

Publications and source records attributed to Peter A Crooks.

At least 37 records · Page 2Linked to original sources
PubMed2005

Identification and synthesis of novel alkaloids from the root system of Nicotiana tabacum: affinity for neuronal nicotinic acetylcholine receptors.

A novel pyridine derivative, 3,5-bis-(1-methyl-pyrrolidin-2-yl)-pyridine, and a pair of diastereomers of 1,1'-dimethyl-[2,3']bipyrrolidinyl were isolated from the root of Nicotiana tabacum plants and identified as novel alkaloids by GC-MS analysis. The structures of these new alkaloids were confirmed by total synthesis. The affinities of these novel alkaloids, and other structurally related compounds for alpha4beta2*, alpha7* neuronal nicotinic acetylcholine receptors (nAChRs), and for nAChRs mediating nicotine-evoked dopamine release from rat striatum were also assessed. The results indicate that these compounds do not interact with alpha7* nAChRs, but inhibit [3H]nicotine binding to the alpha4beta2* nAChR subtype. The results also demonstrate that these compounds act as antagonists at nAChRs mediating nicotine-evoked dopamine release from rat striatum.

Alkaloids↗
PubMed2005

The characterization of a novel rigid nicotine analog with alpha7-selective nAChR agonist activity and modulation of agonist properties by boron inclusion.

The alpha7 nAChR subtype is of particular interest as a potential therapeutic target since it has been implicated as a mediator of both cognitive and neuroprotective activity. The rigid nicotine analog ACME and the N-cyanoborane conjugate ACME-B are selective partial agonists of rat alpha7 receptors expressed in Xenopus oocytes, with no significant activation of either alpha3beta4 or alpha4beta2 receptors. ACME-B is both more potent and efficacious than ACME. The efficacies of ACME-B and ACME are approximately 26% and 10% of the efficacy of ACh, respectively. Similar N-conjugation of S(-)nicotine with cyanoborane decreased efficacy for alpha3beta4 and alpha4beta2 receptors, as well as for alpha7 nAChR. Structural comparison of ACME with the benzylidene anabaseines, another class of previously identified alpha7-selective agonists, suggests that they share a similar structural motif that may be applicable to other alpha7-selective agonists.

Animals↗
PubMed2005

Introduction of unsaturation into the N-n-alkyl chain of the nicotinic receptor antagonists, NONI and NDNI: effect on affinity and selectivity.

N-n-octylnicotinium iodide (NONI) and N-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 the N-n-alkyl chains of NONI and NDNI on inhibition of [3H]nicotine and [3H]methyllycaconitine binding (alpha4beta2* and alpha7* nAChRs, respectively), (86)Rb+ efflux and [3H]DA release (agonist or antagonist effects at alpha4beta2* and alpha6beta2*-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-evoked 86Rb+ efflux, indicating alpha4beta2* antagonism. NONI analogs exhibited a 3-fold to 8-fold greater potency inhibiting nicotine-evoked [3H]DA overflow compared with NONI (IC50 = 0.62 microM; 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-evoked 86Rb+ efflux, indicating antagonism at alpha4beta2* nAChRs. Although NDNI had no effect, NDNB4t and NDNB9e potently inhibited nicotine-evoked [3H]DA overflow (IC50 = 0.02-0.14 microM, Imax = 90%), as did NDNB4c (IC50 = 0.08 microM; Imax = 50%), whereas NDNB3y showed no inhibition. None of the analogs had significant affinity for alpha7* nAChRs. Thus, unsaturated NONI analogs had enhanced affinity at alpha4beta2*- and alpha6beta2*-containing nAChRs, however a general reduction of affinity at alpha4beta2* and an uncovering of antagonist effects at alpha6beta2*-containing nAChRs were observed with unsaturated NDNI analogs.

Aconitine↗
PubMed2005

Defunctionalized lobeline analogues: structure-activity of novel ligands for the vesicular monoamine transporter.

(-)-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.

Animals↗
PubMed2005

Novel antiglaucoma prodrugs and codrugs of ethacrynic acid.

The purpose of this study was to synthesize a novel prodrug of ethacrynic acid (ECA) with short chain polyethylene glycols (PEGs) and codrugs of ECA with the beta-adrenergic blocking agent atenolol (ATL) or timolol (TML) to overcome the adverse effects of ECA and to enhance its physicochemical properties.

Adrenergic beta-Antagonists↗
PubMed2005

(E)-2-Methyl-3-(2-methyl-2-nitrovinyl)-1H-indole and (E)-3-(2-methyl-2-nitrovinyl)-2-phenyl-1H-indole.

In the title compounds, C12H12N2O2, (I), and C17H14N2O2, (II), respectively, the indole rings are planar and the vinyl groups lie out of the indole planes, making dihedral angles of 33.48 (5) and 41.31 (8) degrees , respectively. In (II), the dihedral angle between the phenyl and indole ring planes is 32.06 (6) degrees . In both molecules, the double bond connecting the methylnitrovinyl group and the indole nucleus adopts an E configuration. Notwithstanding the differences in space group [C2/c for (I) and P2(1)2(1)2(1) for (II)], the mode of packing of compounds (I) and (II) is determined by similar intermolecular N-H...O hydrogen-bonding interactions, forming chains that run parallel to [101] in (I) and [001] in (II).

Crystallography, X-Ray↗
PubMed2005

3D-QSAR study of bis-azaaromatic quaternary ammonium analogs at the blood-brain barrier choline transporter.

Previously, we have developed 3D-QSAR models of the blood-brain barrier (BBB) choline transporter, a transport system that may have utility as a vector for central nervous system drug delivery. In this study, we extended the model by evaluating five bis-azaaromatic quaternary ammonium compounds for their affinity for the choline binding site on the BBB-choline transporter. The compounds, and their affinities for the transporter, were then incorporated into our existing molecular model, in order to update our knowledge on the molecular recognition factors associated with interaction of ligands at the choline binding site. The current compounds are structurally related to previous substrates that we have evaluated, but offer additional three dimensional aspects compared to the series of compounds previously utilized to define the original models. The compounds showed good affinity for the BBB-choline transporter, exhibiting inhibition constants ranging from 10 to 68 microM, as determined by the in situ rat brain perfusion method. Comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) methods were used to build the new 3D QSAR models. When the new bis-azaaromatic quaternary ammonium compounds were included in the model, the best cross-validated CoMFA q2 was found to be 0.536 and the non-cross-validated r2 was 0.818. CoMSIA hydrophobic cross-validated q2 was 0.506 and the non-cross-validated r2 was 0.804. This new model was able to better predict BBB-choline transporter affinity of hemicholinium-3 (predicted 65 microM, actual 54 microM), when compared to an earlier model (predicted 316 microM).

Animals↗
PubMed2005

In vitro/in vivo correlation of transdermal naltrexone prodrugs in hairless guinea pigs.

PURPOSE: The purpose of this investigation was to evaluate the in vitro and in vivo percutaneous absorption of the following prodrugs of naltrexone (NTX): 2'-ethylbutyryl-3-O-ester-NTX (ETBUT-ester), methyl-3-O-carbonate-NTX (ME-carbonate), ethyl-3-O-carbamate-NTX (ET-carbamate), and N,N-dimethyl-3-O-carbamate-NTX (DME-carbamate) in hairless guinea pigs. METHODS: In vitro fluxes of NTX and its prodrugs through guinea pig skin were determined using a flow-through diffusion cell system. The pharmacokinetics of NTX prodrugs were determined after topical application of transdermal patches in guinea pigs. RESULTS: All the prodrugs hydrolyzed to NTX on passing through the skin, and ME-carbonate provided the highest NTX flux and had the highest apparent permeability coefficient (K(p)). ME-carbonate and ET-carbamate underwent the highest extent of bioconversion to NTX upon passing through the skin as compared to ETBUT-ester and DME-carbamate. The results of the in vivo studies indicated that a significant amount of NTX was delivered after the application of transdermal patches of NTX prodrugs. A mean steady-state plasma concentration of 7.1 ng/ml was obtained after the application of transdermal patches of ME-carbonate. A good correlation was obtained between the in vitro and in vivo results. CONCLUSIONS: The results of the in vivo studies indicated that the ME-carbonate prodrug of NTX was the most promising drug candidate for transdermal delivery.

Administration, Cutaneous↗
PubMed2005

Lobelane analogues as novel ligands for the vesicular monoamine transporter-2.

A series of lobelane analogues has been synthesized and their structure-activity relationships at the vesicular monoamine transporter-2 (VMAT2) have been evaluated. The most potent analogues in this series were the cis-2,6-piperidino analogues, 25b, 27b, 28b, and 30b, with K(i) values ranging from 430 to 580 nM.

Animals↗
PubMed2005

Human skin permeation of branched-chain 3-0-alkyl ester and carbonate prodrugs of naltrexone.

PURPOSE: Physicochemical characterization and in vitro human skin diffusion studies of branched-chain ester and carbonate prodrugs of naltrexone (NTX) were compared and contrasted with straight-chain ester and carbonate NTX prodrugs. METHODS: Human skin permeation rates, thermal parameters, solubilities in mineral oil and buffer, and stabilities in buffer and plasma were determined. Partition coefficients between stratum corneum and vehicle were determined for straight- and branched-chain esters with the same number of carbon atoms. RESULTS: Branched prodrugs had lower melting points, lower buffer solubilities, and higher mineral oil solubilities than NTX. The transdermal flux values from all of these branched prodrugs were significantly lower than flux values from the straight-chain ester and the methyl carbonate prodrugs. Straight-chain prodrugs had higher partition coefficient values and higher calculated thermodynamic activities than their branched-chain counterparts. The prodrug hydrolysis to NTX in buffer and plasma was slower for prodrugs with increased branching. CONCLUSIONS: Branched-chain prodrugs with bulky moieties had smaller stratum corneum-vehicle partition coefficients and lower thermodynamic activities that resulted in smaller transdermal flux values than straight-chain prodrugs.

Abdomen↗
PubMed2005

In vivo evaluation of 3-O-alkyl ester transdermal prodrugs of naltrexone in hairless guinea pigs.

Naltrexone (NTX) is a potent competitive antagonist with high affinity for the mu-opioid receptor. Therapeutically, NTX is used for the treatment of alcohol dependence and opioid addiction; however, it does not have the ideal physicochemical properties necessary to achieve therapeutic plasma concentrations via the transdermal route. The aim of the present investigation was to evaluate the in vivo transdermal delivery of three 3-O-alkyl ester prodrugs of NTX, including NTX-3-O-acetate (ACE-NTX), NTX-3-O-propionate (PROP-NTX), and NTX-3-O-hexanoate (HEX-NTX) in hairless guinea pigs. The pharmacokinetic parameters for NTX and the 3-O-alkyl ester prodrugs of NTX were determined after intravenous drug administration and topical drug application of transdermal therapeutic systems (TTS) in guinea pigs. The results of the in vivo studies showed mean steady-state plasma concentrations of NTX from NTX, ACE-NTX, PROP-NTX and HEX-NTX at 4.2, 25.2, 16.0, and 8.3 ng/mL, respectively. These NTX plasma concentrations were maintained for 48 h. The results of these in vivo studies demonstrated that ACE-NTX and PROP-NTX prodrugs of NTX were the most promising drug candidates for transdermal delivery.

Acetates↗
PubMed2005

(Z)-3-(1H-Indol-3-yl)-2-(3-thienyl)acrylonitrile and (Z)-3-[1-(4-tert-butylbenzyl)-1H-indol-3-yl]-2-(3-thienyl)acrylonitrile.

(Z)-3-(1H-Indol-3-yl)-2-(3-thienyl)acrylonitrile, C15H10N2S, (I), and (Z)-3-[1-(4-tert-butylbenzyl)-1H-indol-3-yl]-2-(3-thienyl)acrylonitrile, C26H24N2S, (II), were prepared by base-catalyzed reactions of the corresponding indole-3-carboxaldehyde with thiophene-3-acetonitrile. 1H/13C NMR spectral data and X-ray crystal structures of compounds (I) and (II) are presented. The olefinic bond connecting the indole and thiophene moieties has Z geometry in both cases, and the molecules crystallize in space groups P2(1)/c and C2/c for (I) and (II), respectively. Slight thienyl ring-flip disorder (ca 5.6%) was observed and modeled for (I).

Acrylonitrile↗
PubMed2005

Bioconversion of naltrexone and its 3-O-alkyl-ester prodrugs in a human skin equivalent.

The purpose of this study was to compare the percutaneous absorption and bioconversion of naltrexone (NTX), naltrexone-3-O-valerate (VAL), and naltrexone-3-O-(2'-ethylbutyrate) (ETBUT) in a human skin equivalent model (EpiDerm) and in fresh human skin in vitro. NTX diffusion and metabolism to 6-beta-naltrexol (NTXol) were quantitated and compared in the EpiDerm and in excised fresh human skin. VAL and ETBUT diffusion and bioconversion studies were also completed in EpiDerm. Naltrexone bioconverted to levels of 3+/-2% NTXol in the EpiDerm and 1+/-0.5% in fresh human skin. VAL hydrolyzed rapidly in the EpiDerm and mainly (93+/-4%) NTX was found in the receiver compartment, similar to human skin. More intact ETBUT permeated the EpiDerm tissue compared to VAL, and only 15+/-11% NTX was found in the receiver. Significantly higher fluxes of NTX and the prodrugs were observed with the EpiDerm compared to human skin. A similar flux enhancement level was observed for VAL, compared to NTX base, in the EpiDerm and the human skin. Metabolically active human epidermal models like EpiDerm are useful as an alternative experimental system to human skin for prediction of topical/transdermal drug/prodrug bioconversion.

Algorithms↗
PubMed2005

Transdermal delivery of naltrexone and its active metabolite 6-beta-naltrexol in human skin in vitro and guinea pigs in vivo.

The aim of the present study was to evaluate the transdermal delivery of 6-beta-naltrexol (NTXOL), the active metabolite of naltrexone (NTX), across human skin and guinea pig skin in vitro and in hairless guinea pigs in vivo. NTXOL may be responsible for much of NTX's pharmacologic activity. In vitro diffusion studies on NTXOL were compared with similar studies on NTX using a formulation of propylene glycol and buffer in a flow-through diffusion cell system. In vivo guinea pig studies were carried out involving topical application of both drugs in patches containing identical formulations. The in vitro flux of NTX was about 2.3- and 5.6-fold higher than for NTXOL across guinea pig skin and human skin, respectively. NTXOL lag times were longer than NTX in both skin types. In vivo studies in guinea pigs showed that the steady-state plasma level of NTX was twofold greater than NTXOL, which correlated well with in vitro data. The results of the present study indicated that substantial levels of NTX and NTXOL could be delivered via the transdermal route, although the plasma levels of NTXOL were significantly less than NTX. Further transdermal formulation development will be investigated for permeation enhancement.

Administration, Cutaneous↗
PubMed2005

In vitro release studies on matrix type transdermal drug delivery systems of naltrexone and its acetyl prodrug.

Matrix type acrylic adhesive transdermal patches of naltrexone (NTX) and its 3-O-acetyl ester prodrug were prepared and evaluated for drug content, thickness, and in vitro release characteristics. Among the four DURO-TAK adhesive polymers (87-2516, 87-2054, 87-2501, and 87-2582) tested, 87-2516 proved to be the most suitable and compatible polymer for the transdermal delivery of NTX from NTX and prodrug patches. A linear relationship was observed for release flux (F) and cumulative amount (Mt) values versus 1%, 2%, and 3% drug loading at equimolar levels. The release of NTX from the patches showed a good correlation (R2>0.99) for Mt vs. square root t profiles, indicating that a Higuchian matrix diffusion mechanism of drug release from the transdermal adhesive patches was obtained. Overall, the amounts of NTX released from the prodrug patches were significantly higher than from the NTX patches, at all three drug loading levels.

Acetylation↗
PubMed2005

Evaluation of O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyl) 17alpha-hydroxy-5beta-pregnan-20-one as a novel potential antiangiogenic codrug.

Intraocular neovascularization is a complication in a variety of eye diseases, and is a leading cause of visual loss. The purpose of this study was to design and synthesize three novel codrugs of the antiangiostatic steroid, 3alpha, 17alpha, 21-trihydroxy-5beta-pregnan-20-one (trihydroxy steroid, THS) with the cytotoxic agent 5-fluorouracil (5FU) which incorporates either one or two molecules of 5FU attached through carbonate ester linkages at positions O(3), and/or O(21) of the THS molecule. Furthermore, a kinetic study of the O(3alpha)-, O(21)-di-(N(1)-methyloxycarbonyl-2, 4-dioxo-5-fluoropyrimidinyL) 17alpha-hydroxy-5beta-pregnan-20-one (THS-BIS-5FU) codrug was carried out. The overall goal of this codrug strategy was to improve sustained drug delivery of both compounds by overcoming their individual solubility problems, and to thus enhance their bioavailability. The codrug was found to be optimal with superior angiostatic activity using the CAM assay compared to the activity of the parent compounds alone. In the hydrolysis studies 5FU was released at a faster rate than THS with an unknown intermediate observed by HPLC, a rationale and proposed structure and mechanism of the unknown THS derivative is provided.

Angiogenesis Inhibitors↗
PubMed2004

(Z)-2-(1-Phenylsulfonyl-1H-indol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-one and (Z)-(S)-2-(1-phenylsulfonyl-1H-indol-3-ylmethylene)-1-azabicyclo[2.2.2]octan-3-ol.

The title compounds, C22H20N2O3S, (I), and C22H22N2O3S, (II), crystallize in space groups P-1 and P2(1)2(1)2(1), respectively. The indole rings are planar and the benzene ring of the phenylsulfonyl group makes a dihedral angle with the mean plane of the indole ring of 90.2 (2) degrees in (I) and 94.0 (2) degrees in (II). In both molecules, the double bond connecting the aza-bicyclic and indole moieties has a Z geometry. Compound (II) was obtained as an enantiomerically pure crystal and has the 3S configuration.

Aza Compounds↗