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At least 163 records · Page 9Linked to original sources
PubMed2004

Synthesis of [O-methyl-11C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide: a potential PET ligand for CB1 receptors.

Synthesis and in vitro evaluation of [O-methyl-(11)C]1-(2-chlorophenyl)-5-(4-methoxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide ([(11)C]-1), a potential imaging agent for CB(1) receptors using PET is described. 1-(2-Chlorophenyl)-5-(4-hydroxyphenyl)-4-methyl-1H-pyrazole-3-carboxylic acid piperidin-1-ylamide (5), the precursor for radiolabeling, was synthesized from 4-OTBDPS-propiophenone (2) in five steps with 30% overall yield. The reaction of alcohol 5 with [(11)C]MeOTf at 60 degrees C afforded [(11)C]-1 with an average radiochemical yield of 14.5% (EOS) and >2000 Ci/mmol specific activity. The radiotracer was found to selectively label CB(1) receptors in slide-mounted sections of postmortem human brain containing prefrontal cortex as demonstrated by in vitro autoradiography using phosphor imaging.

Autoradiography↗
PubMed2006

Synthesis and dipeptidyl peptidase inhibition of N-(4-substituted-2,4-diaminobutanoyl)piperidines.

In this paper, we report the synthesis of diastereomerically pure N-(4-substituted-2,4-diaminobutanoyl)piperidines. These compounds were prepared to investigate the influence of the 4-substitution on the dipeptidyl peptidase II (DPP II) activity and selectivity of the parent N-(2,4-diaminobutanoyl)piperidine. The (4S)-methyl compound showed subnanomolar inhibition, comparable with the parent compound. The (4R)-methyl group or bigger substituents decreased the activity.

Amination↗
PubMed2006

Synthesis and monoamine transporter affinity of 2beta-carbomethoxy-3beta-(4'-p-substituted phenyl)-piperidine analogs of cocaine.

A series of novel piperidine based analogs of cocaine was synthesized and evaluated in vitro against the three monoamine transporters to develop new potential selective SERT radiotracers. Modification of the phenyl substitution with five-membered heterocyclic groups resulted in a wide affinity and selectivity scale. Radiolabeling and mouse in vivo study was performed on the piperidine analog of ZIENT, which crossed the blood-brain barrier but failed to selectively accumulate in the regions of the brain rich in SERT.

Animals↗
PubMed2006

Benzodiazepine calcitonin gene-related peptide (CGRP) receptor antagonists: optimization of the 4-substituted piperidine.

In our continuing effort to identify CGRP receptor antagonists for the acute treatment of migraine, we have undertaken a study to evaluate alternative 4-substituted piperidines to the lead dihydroquinazolinone 1. In this regard, we have identified the piperidinyl-azabenzimidazolone and phenylimidazolinone structures which, when incorporated into the benzodiazepine core, afford potent CGRP receptor antagonists (e.g., 18 and 29). These studies produced a potent analog (18) which overcomes the instability issues associated with the lead structure 1. A general pharmacophore for the 4-substituted piperidine component of these CGRP receptor antagonists is also presented.

Benzodiazepines↗
PubMed2006

2,4-Disubstituted piperidines as selective CC chemokine receptor 3 (CCR3) antagonists: synthesis and selectivity.

Linear unselective CCR3 antagonist leads with IC(50) values in the 200 nM range were converted into low nM binding compounds selective at CCR3 by moving the piperidine nitrogen substituent to the carbon at the 2-position of the ring. Substitution of the piperidine nitrogen with simple alkyl and acyl groups was found to improve the selectivity of this new compound class. In particular, N-{3-[(2S, 4R)-1-(propyl)-4-(4-fluorobenzyl)piperidinyl]propyl}-N'-(3-acetylphenyl)urea exhibited single digit nanomolar IC(50) values for CCR3 with >100-fold selectivity against an extensive counter screen panel.

Piperidines↗
PubMed2006

2,6-Disubstituted N-arylsulfonyl piperidines as gamma-secretase inhibitors.

A novel piperidine series of gamma-secretase inhibitors, potentially useful for the treatment of Alzheimer's disease, is disclosed. SAR investigation revealed the requirement for cis-stereochemistry of the substituents attached to the core, which resulted in the chair-like diaxial conformation of the piperidine ring. The series was optimized to provide inhibitors with IC(50)'s in the single-digit nanomolar range. Absolute stereochemistry of the active enantiomer was assigned.

Alzheimer Disease↗
PubMed2006

Unusual retention behaviour of 4-substituted piperidines on polybutadiene and polystyrene coated zirconia by comparison to reverse phase silica.

The retention properties of a range of N-methylated and N-des-methyl 4-substituted piperidines on polybutadiene (PBD) and polystyrene (PS) coated zirconia have been studied and compared to those of Xterra RP(18) and Genesis C(18) silica. The effect of buffer type and pH are investigated with regard to the elution order on all three stationary phases. The change in the elution order is linked to the degree of substitution of the piperidine nitrogen and appears to be independent of the rest of the structure, indicating that this moiety is most heavily involved in the separation mechanism on the zirconia phases.

Buffers↗
PubMed2006

Biological evaluation of a technetium-99m-labeled integrated tropane-BAT and its piperidine congener as potential dopamine transporter imaging agents.

INTRODUCTION: Recently, we have reported modification of (99m)Tc-TRODAT-1 by integrating the N2S2 metal chelating unit and the tropane skeleton. Results of a preliminary biodistribution study in rats were promising with respect to brain uptake. The present report deals with the further biological characterization of the (99m)Tc-labelled integrated TRODAT derivatives ((99m)Tc-TropaBAT and (99m)Tc-norchloro-TropaBAT) and with the synthesis and biological evaluation of a novel (99m)Tc-labelled piperidine-based derivative ((99m)Tc-PipBAT). METHODS: Biodistribution of all radiolabelled complexes was studied in normal mice. A more detailed ex vivo intracerebral distribution study of the two (99m)Tc-TropaBAT complexes was additionally performed in normal rats. Autoradiography of brain sections of normal mice (with or without pretreatment with FP-beta-CIT or haloperidol) and rats was performed. Affinity for the dopamine transporter (DAT) was also assessed in vitro in the presence or absence of cocaine. RESULTS: Both (99m)Tc-TropaBAT complexes show a slightly higher brain uptake than (99m)Tc-TRODAT-1, but the striatum/cerebellum activity ratio is less favourable. Nevertheless, significant striatal uptake was detected after ex vivo autoradiography, but this uptake was also observed after pretreatment with FP-beta-CIT. Unexpectedly, no striatal uptake was detected after in vitro incubation of mouse brain sections with the tracer agents. For (99m)Tc-PipBAT, neither brain uptake nor in vitro striatal uptake was found. CONCLUSION: Both (99m)Tc-TropaBAT complexes exhibit similar diffusion into brain as (99m)Tc-TRODAT-1, and ex vivo autoradiography shows significant striatal uptake. However, the inferior striatum/cerebellum activity ratio, the striatal uptake in mice pretreated with FP-beta-CIT or haloperidol, and the lack of striatal uptake during in vitro incubation prove that the DAT is not targeted. Brain uptake disappears when the tropane skeleton is replaced by a piperidine ring, and also in this case no striatal uptake is found in vitro.

Animals↗
PubMed2002

Spiro[1,2,4-benzotriazine-3(4H),4'-(1'-substituted)piperidines] and related compounds as ligands for sigma receptors.

As analogues of some conformationally restricted spiropiperidine derivatives which are endowed with high affinity for sigma1 receptor, a set of 16 spiro[1,2,4-benzotriazine-3(4H),4'-(1'-substituted)piperidines] and congeneric compounds was prepared and tested for affinity to sigma1 receptor subtype. All N-arylalkyl substituted derivatives exhibited high affinity for the relevant receptor, with Ki in the low nanomolar range. Affinity for sigma2 subtype (assayed only for a few representative compounds) was from one to three order of magnitude lower. Spiro[1,2,4-benzotriazine-3(4H),4'-(1'-benzyl)piperidine] (2), with a ratio Ki sigma2/Ki sigma1 = 7000 should represent the most selective sigma1 ligand so far described.

Indicators and Reagents↗
PubMed1993

Quinolizidine and piperidine alkaloid teratogens from poisonous plants and their mechanism of action in animals.

Quinolizidine and piperidine alkaloid teratogens from Lupinus, Conium, and Nicotiana genera have been identified as causes of birth defects in livestock induced by poisonous plants. Many defects now known to be related to poisonous plant ingestion were once thought to have a genetic origin. This supposition delayed diagnosis, reporting, and understanding of such birth defects, because breeders and producers feared the news would make it difficult to sell breeding stock. Defects caused by quinolizidine and piperidine teratogens include cleft palate and contracture-type skeletal defects such as arthrogryposis, scoliosis, torticollis, and kyphosis. Teratogens have been identified, differences in susceptibility to teratogenic compounds among livestock species have been elucidated, periods of gestation when specific types of birth defects occur have been determined, and information about mechanism of action has been developed.

Alkaloids↗
PubMed2000

Diphenylsulfone muscarinic antagonists: piperidine derivatives with high M2 selectivity and improved potency.

Piperidine analogues of our previously described piperazine muscarinic antagonists are described. Piperidine analogues show a distinct structure-activity relationship (SAR) that differs from comparable piperazines. Compounds with high selectivity and improved potency for the M2 receptor have been identified. The lead compound, 12b, increases acetylcholine release in vivo. Compounds of this class may be useful for the treatment of cognitive disorders such as Alzheimer's disease (AD).

Acetylcholine↗
PubMed2001

Sar studies of piperidine-based analogues of cocaine. Part 3: oxadiazoles.

The synthesis of novel 4beta-aryl-1-methyl-3alpha-(3-substituted-1,2,4-oxadiazol-5-yl)piperidines, bioisosteres of ester (+)-1, is described. The synthesized oxadiazoles were evaluated for their affinity to the DAT and their ability to inhibit monoamine reuptake at the DAT, NET, and 5HTT. The results show that affinity to the DAT and ability to inhibit the reuptake at the DAT, NET, and 5HTT is a function of the size of the substituent in the oxadiazole ring. (+)-(3R,4S)-4beta-(4-Chlorophenyl)-1-methyl-3alpha-(3-methyl-1,2,4-oxadiazol-5-yl)piperidine [(+)-2a], which is structurally and pharmacologically most similar to the ester (+)-1 in this series, showed at least a 2-fold longer duration of action when compared to ester (+)-1.

Carrier Proteins↗
PubMed2001

Rational design and synthesis of novel 2,5-disubstituted cis- and trans-piperidine derivatives exhibiting differential activity for the dopamine transporter.

Herein, we report the rational design and synthesis of novel 2,5-disubstituted piperidine derivatives in the cis and trans isomeric forms. Out of these two isomers, the cis-isomer, 7a, was found to exhibit the most potent activity and selectivity for the dopamine transporter. These novel derivatives represent conformationally constrained version of piperidine analogue of GBR compounds.

Benzhydryl Compounds↗
PubMed1999

Synthesis of 2-(2-adamantyl)piperidines and structure anti-influenza virus A activity relationship study using a combination of NMR spectroscopy and molecular modeling.

The 2-(2-adamantyl)piperidines 13 and 15a-c were synthesized and evaluated for anti-influenza virus A and B activity. The parent N-H compound 13 was 3-4 times more active than amantadine and rimantadine against H2N2 influenza A. N-alkylation of 13 resulted in derivatives 15a-c that were devoid of biological activity. This dramatic reduction in biological activity may be attributed to the different conformational properties between N-H and N-alkyl piperidines, as deduced from the combination of computational chemistry and NMR spectroscopy.

Animals↗
PubMed2001

Novel (4-piperidin-1-yl)-phenyl sulfonamides as potent and selective human beta(3) agonists.

A series of novel (4-piperidin-1-yl)-phenyl sulfonamides was prepared and evaluated for their biological activity on the human beta(3)-adrenergic receptor (AR). Replacement of the 3,4-dihydroxyl group of the catechol moiety with 4-hydroxyl-3-methyl sulfonamide on the left-hand side of the compounds resulted in a number of potent full agonists at the beta(3) receptor. Modification of the right-hand side of the compounds by incorporation of a free carboxylic acid resulted in a few potent human beta(3) agonists with low affinities for beta(1)- and beta(2)-ARs. N-Alkyl substitution on the 4-piperidin-1-yl-phenylamine further increased the beta(3) potency while maintaining the selectivity. For example, sulfonamide 48 is a potent full beta(3) agonist (EC(50)=0.004 microM, IA=1.0) with > 500-fold selectivity over beta(1)- and beta(2)-ARs.

Adrenergic beta-3 Receptor Agonists↗