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PubMed2004

Studies toward labeling cytisine with [11C]phosgene: rapid synthesis of a delta-lactam involving a new chemoselective lithiation-annulation method.

With the aim of the radiolabeling of cytisine, a potent agonist of nicotinic receptors, with [(11)C]phosgene, the rapid synthesis of a lactam model of our target has been studied. The key step of the delta-lactam formation is a new chemoselective lithiation-annulation method, under high dilution, of a suitable piperidinylcarbamoyl chloride. This precursor was obtained from (2-hydroxyethyl)piperidine in a linear synthetic sequence involving a Corey-Fuchs olefination of the corresponding aldehyde, followed by a selective reduction, using a diimide equivalent, of an iodoalkyne into a (Z)-iodopropene piperidine. This alkene served as main precursor to study the cyclization according to several procedures using phosgene as the required carbonylating reagent.

Alkaloids↗
PubMed2004

4-(9-fluorenylmethyloxycarbonyl)phenylhydrazine (FmPH): a new chromophoric reagent for quantitative monitoring of solid-phase aldehydes(1-3).

A direct method for quantifying solid-phase aldehydes has been developed, using a new reagent, 4-(9-fluorenylmethyloxycarbonyl)phenylhydrazine (FmPH). The FmPH reagent was synthesized in three steps (24% overall yield) from commercially available p-hydrazinobenzoic acid. Resin-bound aldehydes reacted quantitatively with FmPH, in the presence of trimethylorthoformate (TMOF) as a dehydrating agent, to form a highly conjugated, immobilized FmPH-hydrazone. Next, mild treatment of the hydrazone with an excess of piperidine-N,N-dimethylformamide (1:1) released the piperidine-dibenzofulvene adduct chromophore (epsilon(301nm) = 7800 M(-1) cm(-1)) from the support. FmPH quantitation of aldehydes proved to be a straightforward, sensitive, and reproducible technique for monitoring resin-bound aldehydes [albeit insufficiently reactive to allow reliable quantification of ketones]. The FmPH aldehyde assay is applicable to a range of solid supports, as demonstrated specifically for poly(ethylene glycol)-polystyrene (PEG-PS), aminomethylpolystyrene (AMP), and cross-linked ethoxylate acrylate resin (CLEAR).

Aldehydes↗
PubMed2005

Regioselective oxygenative tetraamination of [60]fullerene. Fullerene-mediated reduction of molecular oxygen by amine via ground state single electron transfer in dimethyl sulfoxide.

The reaction of [60]fullerene with a variety of a secondary aliphatic amines in 20% v/v dimethyl sulfoxide in chlorobenzene under an atmospheric pressure of molecular oxygen allows regioselective introduction of four amino groups and one epoxide group around one pentagon of the fullerene molecule in good to high yield. This new synthesis of tetraaminofullerene expoxide can be carried out with a simple procedure on a multigram scale at room temperature and affords a variety of functionalized fullerene derivatives. Near-infrared analysis of a mixture of [60]fullerene and piperidine in a deaerated dimethyl sulfoxide/chlorobenzene mixture indicated equilibrium formation of [60]fullerene radical anion (C60*-) that persists at least for 2 weeks at room temperature but reacts immediately with molecular oxygen to give the tetraaminofullerene expoxide. The Benesi-Hildebrand analysis of the concentration dependency of the near-infrared absorption indicated that a [C60*- piperidine*+] radical ion pair is formed with an equivalent constant of K = 0.62 +/- 0.02 M(-1) at 25 degrees C. This and other lines of evidence suggest that the oxygenative amination reaction involves C60-mediated reduction of molecular oxygen by the amine.

Journal Article↗
PubMed2006

Synthesis of new nitrogen analogues of salacinol and deoxynojirimycin and their evaluation as glycosidase inhibitors.

The synthesis of two enantiomerically pure iminosugars, analogues of 1-L-deoxynojirimycin (l-DNJ) and 1-D-deoxymannojirimycin (DMJ), was achieved using cyclic sulfate substituted isoxazoline derivatives. The piperidine ring was formed via the reduction of an isoxazoline into an amine which underwent a spontaneous intramolecular cyclization by reaction with the cyclic sulfate moiety. The nucleophilic attack of these two trisubstituted piperidines and morpholine on L- and D-erythritol-1,3-cyclic sulfates gave six new nitrogen analogues of salacinol. The inhibitory properties of the synthesized salacinol analogues were evaluated on several commercial glycosidases.

1-Deoxynojirimycin↗
PubMed2006

A diastereoselective radical cyclization approach to substituted quinuclidines.

A new, concise, and flexible approach to novel quinuclidines has been developed, which employs a phosphorus hydride mediated radical addition/cyclization reaction in the key step. 1,7-Diene 5 reacts with diethyl thiophosphite in an efficient and diastereoselective radical addition/cyclization reaction to give trisubstituted piperidines 4ab. Piperidines 4ab are subsequently converted into 2,5-disubstituted quinuclidines using S(N)2-type cyclizations. Finally, the resulting quinuclidines are shown to undergo novel Horner-Wadsworth-Emmons-type (HWE-type) reactions to give unsaturated quinuclidines 21a and 21b, which have structures similar to that of (-)-quinine 1.

Cyclization↗
PubMed1997

Theoretical Insights Regarding the Cycloaddition Behavior of Push-Pull Stabilized Carbonyl Ylides.

A series of diazoamido keto esters were prepared by the reaction of N-substituted 3-carbethoxy-2-piperidone with n-butylmagnesium chloride followed by the addition of ethyl 2-diazomalonyl chloride. Treatment of these diazo amides with rhodium(II) acetate afforded transient push-pull carbonyl ylide dipoles which could be readily trapped with electron deficient dipolarophiles. All attempts to induce the dipolar cycloaddition to occur across tethered alkenyl pi-bonds failed to give internal cycloadducts. However, placing a sp(2) center on the tethered side chain was found to result in the formation of a tricyclic adduct in 95% yield. The stereochemistry of the cycloadduct was firmly established by an X-ray crystallographic study and occurred endo with respect to the amido carbonyl ylide dipole. A detailed computational study was undertaken to provide better insight into the factors that influence the intramolecular cycloaddition process. The calculations indicate that a severe cross-ring 1,3-diaxial interaction caused by the bridgehead methyl group promotes a boat or twist-boat conformation in the piperidine ring fused to the newly forming one. The presence of a carbonyl group in the dipolarophile tether helps to relieve the steric congestion by virtue of favoring a second boat in the latter ring. Without the C=O group, both nascent and piperidine rings are in the chair conformation at lowest energy, and the reaction barrier is disadvantaged by 5.6 kcal/mol, allowing other competing processes to intervene.

Journal Article↗
PubMed1999

Conformational Switching and the Synthesis of Spiro[2H-indol]-3(1H)-ones by Radical Cyclization.

Radical cyclization of 1-(2-bromophenylamino)cyclohexanecarbonitriles (3, X = CH) and 4-(2-bromophenylamino)-4-piperidinecarbonitriles (3, X = N) provide spiro[2H-indole-2-cyclohexan]-3(1H)-imines (5, X = CH) and spiro[2H-indole-2,4'-piperidin]-3(1H)-imines (5, X = N), respectively, in 33-57% yields. This contradicts a recent report that 1-(2-bromophenylamino)cyclohexanecarbonitrile (3, X-R(2) = CH(2)), treated under apparently identical conditions, led only to nitrile transfer product 6 (X-R(2) = CH(2)). Acidic hydrolyses of the imines provide the corresponding ketones 2 in quantitative yields. Single-crystal X-ray analyses of ketone 2e and nitrile 3e indicate that the relative configuration of the aromatic nitrogen has been inverted during the cyclization. In addition, NOE NMR analyses of spiroindolepiperidine 2c and its aniline-nitrogen-methylated analogue 10a show that the relative conformation of the piperidine ring has inverted. Thus, methylation of 2c acts as a conformational "switch" for the spiroindolepiperidine ring system.

Journal Article↗
PubMed2005

Alkaloids from amphibian skin: a tabulation of over eight-hundred compounds.

A diverse array of biologically active, lipid-soluble alkaloids have been discovered in amphibian skin. Such alkaloids include the following: the steroidal samandarines from salamanders, the batrachotoxins, histrionicotoxins, gephyrotoxins, and epibatidine from neotropical poison frogs (Dendrobatidae), the pumiliotoxins, allopumiliotoxins, homopumiliotoxins, and decahydroquinolines from certain genera of anurans from four families (Dendrobatidae, Mantellidae, Bufonidae, and Myobatrachidae), a variety of izidines (pyrrolizidines, indolizidines, quinolizidines, lehmizidines), pyrrolidines, piperidines, various tricyclics (related in structures to the coccinellines), and spiropyrrolizidines from the first three of these four families, the pseudophrynamines from one genus of Australian frogs, and a variety of unclassified alkaloids as yet of undetermined structure. With the exception of the samandarines and the pseudophrynamines, all alkaloids appear to be derived from dietary sources. Although only a few of the over 800 amphibian skin alkaloids have been detected in arthropods, putative arthropod sources for the batrachotoxins and coccinelline-like tricyclics (beetles), the pumiliotoxins (ants, mites), the decahydroquinolines, izidines, pyrrolidines, and piperidines (ants), and the spiropyrrolizidines (millipedes) have been discovered. Ants are likely sources for histrionicotoxins, lehmizidines, and tricyclic gephyrotoxins. Epibatidines represent an important alkaloid class without a putative dietary source. The structures for many of these alkaloids have been rigorously established, while the structures of others represent tentative proposals, based only on mass spectral and FTIR spectral data, along with analogies to structures of well-defined alkaloids.

Alkaloids↗
PubMed2000

Tandem Aza

The alpha-hydroxyalkyl piperidine unit is common to several naturally occurring alkaloids and azasugar analogues. Polysubstituted piperidine derivatives of this kind (3), embodying four stereogenic centers, are formed in just a single operation from the highly stereocontrolled reaction of 4-borono-1-azadienes (1), maleimides, and aldehydes. This novel multicomponent reaction which affords as many as four elements of diversity should prove highly valuable in combinatorial chemistry and natural product synthesis.

Journal Article↗
PubMed2005

Diastereoselective synthesis of 4-hydroxypiperidin-2-ones via Cu(I)-catalyzed reductive aldol cyclization.

[chemical reaction: see text]. 4-Hydroxypiperidin-2-ones may be prepared in highly diastereoselective fashion using a Cu(I)-catalyzed reductive aldol cyclization of alpha,beta-unsaturated amides with ketones. Used in combination with proline-catalyzed asymmetric Mannich reactions, this methodology enables the enantioselective synthesis of more highly functionalized piperidin-2-ones and hydroxylated piperidines.

Journal Article↗
PubMedDate not supplied

DNA damage induced by metabolites of o-phenylphenol in the presence of copper(II) ion.

Reactivities of o-phenylphenol and its metabolites (2,5-dihydroxybiphenyl, 2-phenyl-1,4-benzoquinone) with DNA were investigated by a DNA sequencing technique, and the reaction mechanism was studied by UV-visible and ESR spectroscopies. In the presence of Cu(II), 2,5-dihydroxybiphenyl caused strong DNA damage even without piperidine treatment. Catalase, methionine, and methional inhibited the DNA damage completely, whereas mannitol, sodium formate, ethanol, tert-butyl alcohol, and superoxide dismutase did not. 2,5-Dihydroxybiphenyl plus Cu(II) frequently induced a piperidine-labile site at thymine and guanine residues. The addition of Fe(III), Mn(II), Co(II), Ni(II), Zn(II), Cd(II), or Pb(II) did not induce DNA damage with 2,5-dihydroxybiphenyl. When H2O2 was added, 2-phenyl-1,4-benzoquinone also induced DNA damage in the presence of Cu(II). Cu(II) accelerated the autoxidation of 2,5-dihydroxybiphenyl to quinone. An ESR study revealed that the semiquinone radical is an intermediate of the autoxidation. Catalase had no inhibitory effect on the acceleration by Cu(II). Superoxide dismutase promoted both the autoxidation of 2,5-dihydroxybiphenyl and the initial rate of semiquinone radical production. ESR spin trapping experiments showed that the addition of Fe(III) produced hydroxyl radical during the autoxidation of 2,5-dihydroxybiphenyl, whereas the addition of Cu(II) hardly did so. The results suggest that DNA damage by 2,5-dihydroxybiphenyl plus Cu(II) is due to active species other than hydroxyl free radical.

Benzoquinones↗
PubMed1997

Dietary secondary amines and liver hepatoma in Port Harcourt, Nigeria.

Dietary secondary amines of some Nigerian foodstuffs were analyzed by Soxhlet extraction, using petroleum ether (b.p. 60-80 degrees C); followed by thin layer chromatography developed in a solvent system; n-butanol: 95% ethanol: water (4:2:1) for the qualitative test. Each UV fluorescent band in the test chromatogram was scraped and eluted with distilled water, filtered and assayed for secondary amine content for the quantitative test. Quantitative estimations were by the colorimetric methods. The results show that Ugu--Telfairia occidentalo; millet--Panicum miliaceum; bitter leaf--Vernonia amygdalina; mushroom--Boletus spp; and Okro--Hibiscus esculentus contain diethylamine, dimethylamine, morpholine and ethylaniline. Garri--Manihot utilissima flour contains diethylamine and dimethylamine only; while fish (frozen) Tilapia malanopleura contains diethylamine, dimethylamine and piperidine and the smoked fish--Tilapia nilotica contains diethylamine, dimethylamine, ethylaniline, morpholine, piperidine and n-propylamine. Cocoyam--Xanthosoma sagittifolium contains diethylamine, dimethylamine, morpholine, ethylaniline and proline. The results also show that the secondary amine content of the various foodstuffs ranged between 0.80-0.91 microg N/kg. The public health implications of these findings are discussed.

Amines↗
PubMed2001

Transport of peptidomimetic thrombin inhibitors with a 3-amidino-phenylalanine structure: permeability and efflux mechanism in monolayers of a human intestinal cell line (Caco-2).

PURPOSE: Peptidomimetic thrombin inhibitors derived from Nalpha-(2-naphthylsulfonyl)-3-amidino-phenylalanine with different basic and acidic substituents were investigated with respect to their intestinal transport behavior. METHODS: Intestinal permeability coefficients were studied using Caco-2 monolayers and a reversed-phase HPLC method for quantitation. RESULTS: Apparent permeability coefficients Papp of compounds with a free amidino group were in general low (<10 x 10(-8) cm/s) and independent of the structure of the amide part (C-terminus). Polarized efflux, however, was strongly affected by substituents in the amide moiety yielding the following efflux ratios (ER): methylpiperidide (1) (ER 45) > piperidine carboxylic acid methylester (ER 6-11) > piperidine carboxylic acids (ER 1.9-2.9) > piperazide (ER -0.17). Efflux of (1) was temperature-dependent, but independent of the enantiomeric configuration, accompanied by an increase in transepithelial electrical resistance (TEER), and could be reduced by P-gp inhibitors (PSC 833, Cremophor EL) but not by indomethacin. Replacement of the amidine group of (1) by aminomethyl-, amino-, and oxamidine- moieties drastically increased absorptive permeability (46-68 fold) with ER < 3.4. In contrast, the oxamidine with a C-terminal nipecotic acid residue (8) displayed also a temperature dependent efflux- without altering TEER (ER 22). This efflux was sensitive to PSC833/Cremophor EL and indomethacin. CONCLUSIONS: Basic and acidic residues of amidino-phenylalanine-derived thrombin inhibitors mediate affinity to intestinal efflux pumps. presumably P-gp and MRP. P-gp mediated efflux was related to a net positive charge and accompanied by an increased TEER. Among the methylpiperide (1) promoieties studied the oxamidino group seems to be very promising in overcoming both transport and efflux problems frequently encountered with peptidomimetics containing amidines.

Amidines↗
PubMed2001

Computational model of the complex between GR113808 and the 5-HT4 receptor guided by site-directed mutagenesis and the crystal structure of rhodopsin.

A computational model of the transmembrane domain of the human 5-HT4 receptorcomplexed with the GR113808 antagonist was constructed from the crystal structure of rhodopsin and the putative residues of the ligand-binding site, experimentally determined by site-directed mutagenesis. The recognition mode of GR113808 consist of: (i) the ionic interaction between the protonated amine and Asp3.32; (ii) the hydrogen bond between the carbonylic oxygen and Ser5.43; (iii) the hydrogen bond between the ether oxygen and Asn6.55; (iv) the hydrogen bond between the C-H groups adjacent to the protonated piperidine nitrogen and the pi electrons of Phe6.51; and (v) the pi-sigma aromatic-aromatic interaction between the indole ring and Phe6.52. This computational model offers structural indications about the role of Asp3.32, Ser5.43, Phe6.51, Phe6.52, and Asn6.55 in the experimental binding affinities. Asp3.32Asn mutation does not affect the binding of GR113808 because the loss of binding affinity from an ion pair to a charged hydrogen bond is compensated by the larger energetical penalty of Asp to disrupt its side chain environment in the ligand-free form, and the larger interaction between Phe6.51 and the piperidine ring of the ligand in the mutant receptor. In the Phe6.52Val mutant the indole ring of the ligand replaces the interaction with Phe6.52 by a similarly intense interaction with Tyr5.38, with no significant effect in the binding of GR113808. The mutation of Asn6.55 to Leu replaces the hydrogen bond of the ether oxygen of the ligand from Asn6.55 to Cys5.42, with a decrease of binding affinity that approximately equals the free energy difference between the SH...O and NH...O hydrogen bonds. Because these residues are also present in the other members of the neurotransmitter family of G protein-coupled receptors, these findings will also serve for our understanding of the binding of related ligands to their cognate receptors.

Amino Acid Sequence↗
PubMed2004

Characterization and metal affinity of Tirofiban, a pharmaceutical compound used in acute coronary syndromes.

The crystal and molecular structure of Tirofiban [N-(n-butanesulfonyl)-O-(4-(4-piperidinyl)-butyl)-(S)-tyrosine] is here reported. In the solid state the carboxylic group is in the anionic form while the piperidine molecule appear in the protonated form. By H NMR spectroscopy and potentiometric study three pKa are found: pKa(COOH) = 3.1 (1), pKa(NHPIP) = 11.6(1) and pKa(NHSO2) = 13.8(1). The complexing ability of Tirofiban towards various metal ions (Cu(II), Ni(II), Co(II), Cd(II), Pb(II), Zn(II) and Ca(II)) is also determined by means of potentiometric studies. The prevailing species are [M(TirH)2]2+ where the ligand coordinates the metal ion through carboxylic group, while the piperidine nitrogen is still protonated. The great stability of these complexes may be due to the presence of hydrogen bond interactions, as well as the formation of stacking interactions involving the phenyl ring of the tyrosine residue.

Coronary Disease↗
PubMed1997

Antinociceptive and immunosuppressive effects of opiate drugs: a structure-related activity study.

1. Although it is well known that morphine induces significant immunosuppression, the potential immunosuppressive activity of morphine derived drugs commonly used in the treatment of pain (codeine, hydromorphone, oxycodone) has never been evaluated. 2. We evaluated in the mouse the effect of the natural opiates (morphine and codeine) and synthetic derivatives (hydromorphone, oxycodone, nalorphine, naloxone and naltrexone) on antinociceptive thresholds and immune parameters (splenocyte proliferation, Natural Killer (NK) cell activity and interleukin-2 (IL-2) production). 3. Morphine displayed a potent immunosuppressive effect that was not dose-related to the antinociceptive effect, codeine possessed a weak antinociceptive effect and limited immunosuppressive activity; nalorphine, a mu-antagonist and kappa-agonist, exerted a potent immunosuppressive effect, but had very weak antinociceptive activity. The pure kappa-antagonist nor-BNI antagonized the antinociceptive, but not the immunosuppressive effect of nalorphine. 4. Hydromorphone and oxycodone, potent antinociceptive drugs, were devoid of immunosuppressive effects. 5. The pure antagonists naloxone and naltrexone potentiated immune responses. 6. Our data indicate that the C6 carbonyl substitution, together with the presence of a C7-8 single bond potentiates the antinociceptive effect, but abolishes immunosuppression (hydromorphone and oxycodone). 7. The single substitution of an allyl on the piperidinic ring resulted in a molecule that antagonized the antinociceptive effect but maintained the immunosuppressive effect. 8. Molecules that carry modifications of C6, the C7-8 bond and C14, together with an allyl or caboxymethyl group on the piperidinic ring antagonized both the antinociceptive and the immunosuppressive effect of opiates and were themselves immunostimulants.

Animals↗
PubMed1997

Species differences in brain adenosine A1 receptor pharmacology revealed by use of xanthine and pyrazolopyridine based antagonists.

1. The pharmacological profile of adenosine A1 receptors in human, guinea-pig, rat and mouse brain membranes was characterized in a radioligand binding assay by use of the receptor selective antagonist, [3H]-8-cyclopentyl-1,3-dipropylxanthine ([3H]-DPCPX). 2. The affinity of [3H]-DPCPX binding sites in rat cortical and hippocampal membranes was similar. Binding site affinity was higher in rat cortical membranes than in membranes prepared from guinea-pig cortex and hippocampus, mouse cortex and human cortex. pKD values (M) were 9.55, 9.44, 8.85, 8.94, 8.67, 9.39 and 8.67, respectively. The binding site density (Bmax) was lower in rat cortical membranes than in guinea-pig or human cortical membranes. 3. The rank order of potency of seven adenosine receptor agonists was identical in each species. With the exception of 5'-N-ethylcarboxamidoadenosine (NECA), agonist affinity was 3.5-26.2 fold higher in rat cortical membranes than in human and guinea-pig brain membranes; affinity in rat and mouse brain membranes was similar. While NECA exhibited 9.3 fold higher affinity in rat compared to human cortical membranes, affinity in other species was comparable. The stable GTP analogue, Gpp(NH)p (100 microM) reduced 2-chloro-N6-cyclopentyladenosine (CCPA) affinity 7-13.9 fold, whereas the affinity of DPCPX was unaffected. 4. The affinity of six xanthine-based adenosine receptor antagonists was 2.2-15.9 fold higher in rat cortical membranes compared with human or guinea-pig membranes. The rank order of potency was species-independent. In contrast, three pyrazolopyridine derivatives, (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-2-piperidine ethanol (FK453), (R)-1-[(E)-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl) acryloyl]-piperidin-2-yl acetic acid (FK352) and 6-oxo-3-(2-phenylpyrazolo[1,5-a]pyridin-3-yl)-1(6H)-pyridazinebutyric acid (FK838) exhibited similar affinity in human, guinea-pig, rat and mouse brain membranes. pKi values (M) for [3H]-DPCPX binding sites in human cortical membranes were 9.31, 7.52 and 7.92, respectively. 5. Drug affinity for adenosine A2A receptors was determined in a [3H]-2-[4-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamido ade nosine ([3H]-CGS 21680) binding assay in rat striatal membranes. The pyrazolopyridine derivatives, FK453, FK838 and FK352 exhibited pKi values (M) of 5.90, 5.92 and 4.31, respectively, compared with pKi values of 9.31, 8.18 and 7.57 determined in the [3H]-DPCPX binding assay in rat cortical membranes. These novel pyrazolopyridine derivatives therefore represent high affinity, adenosine A1 receptor selective drugs that, in contrast to xanthine based antagonists, exhibit similar affinity for [3H]-DPCPX binding sites in human, rat, mouse and guinea-pig brain membranes.

Adenosine↗
PubMed2003

Endothelium-independent relaxation to cannabinoids in rat-isolated mesenteric artery and role of Ca2+ influx.

(1) Three cannabinoid receptor agonists, anandamide (CB(1) receptor-selective) and the aminoalkyl-indoles, JWH 015(2-methyl-1-propyl-1H-indol-3-yl)-1-napthalenylmethanone; (CB(2) receptor-selective), R-(+)-WIN 55,212-2 (R-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; slightly CB(2) receptor-selective), as well as the enantiomer S-(-)-WIN 55,212-3(S-(-)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolol[1,2,3-de]-1,4-benzoxazin-6-yl]-1-napthalenylmethanone; inactive at cannabinoid receptors), induced endothelium-independent relaxation of methoxamine-precontracted isolated small mesenteric artery of rat. KCL (60 mM) precontraction did not affect relaxation to the aminoalkylindoles, but reduced that to anandamide. (2) SR14176A (N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; 3 micro M; CB(1) receptor antagonist) inhibited relaxation only to JWH 015 and anandamide. Neither AM 251 (N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; CB(1) antagonist) nor SR 144528 (N-[(1S)-endo-1,3,3-trimethyl bicyclo[2.2.1] heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide; CB(2) antagonist; both at 3 micro M) affected any of the relaxations. (3) Vanilloid receptor desensitisation with capsaicin reduced anandamide relaxation; addition of SR 141716A (3 micro M) then caused further inhibition. SR 141716A did not affect capsaicin-induced relaxation. (4) The aminoalkylindoles inhibited CaCl(2)-induced contractions in methoxamine-stimulated vessels previously depleted of intracellular Ca(2+). These inhibitory effects were greatly reduced or abolished in ionomycin-(a calcium ionophore) contracted vessels. Anandamide also caused vanilloid receptor-independent, SR 141716A- (3 micro M) insensitive, inhibition of CaCl(2) contractions. (5) In conclusion, the aminoalkylindoles JWH 015, R-(+)-WIN 55,212-2 and S-(-)-WIN 55,212-3 relax rat small mesenteric artery mainly by inhibiting Ca(2+) influx into vascular smooth muscle. Anandamide causes vasorelaxation by activating vanilloid receptors, but may also inhibit Ca(2+) entry. Relaxation to JWH 015 and anandamide was sensitive to SR 141716A, but there is no other evidence for the involvement of CB(1) or CB(2) receptors in responses to these compounds.

Animals↗