piperidines and 4-phenylpiperidine

A series of mono-substituted 4-phenylpiperidines and -piperazines have been synthesized and their effects on the dopaminergic system tested in vivo. The structure activity relationship (SAR) revealed that the position and physicochemical character of the aromatic substituent proved to be critical for the levels of 3,4-dihydroxyphenylacetic acid (DOPAC) in the brain of freely moving rats. In order to investigate how the structural properties of these compounds affect the response, a set of tabulated and calculated physicochemical descriptors were modeled against the in vivo effects using partial least square (PLS) regression. Furthermore, the binding affinities to the dopamine D2 (DA D2) receptor and monoamine oxidase A (MAO A) enzyme were determined for a chosen subset and QSAR models using the same descriptors as in the in vivo model were produced to investigate the mechanisms leading to the observed DOPAC response. These models, in combination with a strong correlation between the levels of striatal DOPAC and the affinities to DA D2 and MAO A, provides a comprehensive understanding of the biological response for compounds in this class.

Topics: Animals; Dopamine Agonists; Dose-Response Relationship, Drug; Humans; Least-Squares Analysis; Molecular Structure; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Piperazines; Piperidines; Quantitative Structure-Activity Relationship; Rats; Receptors, Dopamine D2; Structure-Activity Relationship

This Letter describes the synthesis of two regioisomers of a new class of vesamicol analogs as possible ligands for imaging the vesicular acetylcholine transporter in future PET studies. The two pyrrolovesamicols (±)-6a and (±)-6b were synthesized by nucleophilic ring opening reaction of a tetrahydroindole epoxide precursor with 4-phenylpiperidine. The reaction mechanism of the synthesis was studied by HPLC and the molecular structures were determined by X-ray structure analysis. Unexpected low binding affinities to VAChT (K(i)=312±73 nM for (±)-6a and K(i)=7320±1840 nM for (±)-6b) were determined by competitive binding analysis using a cell line stably transfected with ratVAChT and (-)-[(3)H]vesamicol.

Topics: Animals; Binding Sites; Binding, Competitive; Cell Line; Chromatography, High Pressure Liquid; Contrast Media; Crystallography, X-Ray; Epoxy Compounds; Fluorine Radioisotopes; Humans; Ligands; Molecular Structure; Piperidines; Positron-Emission Tomography; Pyrroles; Rats; Stereoisomerism; Tritium; Vesicular Acetylcholine Transport Proteins

Non-activated 2-(4-chloro-2-cyano-2-phenylbutyl)aziridines were used as building blocks for the stereoselective synthesis of novel cis-2-cyanomethyl-4-phenylpiperidines via a microwave-assisted aziridine to piperidine ring expansion followed by a radical-induced nitrile translocation through initial formation and subsequent cleavage of intermediate bicyclic iminyl radicals. Furthermore, these 2-(cyanomethyl)piperidines were shown to be eligible substrates for the preparation of methyl cis-(1-arylmethyl-4-piperidin-2-yl)acetates through a Pinner reaction using gaseous HCl in methanol.

Topics: Acetates; Aziridines; Methylation; Nitriles; Piperidines; Stereoisomerism

A facile synthesis for novel loperamide analogs as potential μ opioid receptors is described. The synthetic procedure for compound 5, which contains two 4-phenyl piperidine scaffolds, was optimized, and this compound was synthesized in excellent yield. We also describe a mild and highly efficient protocol for the synthesis of compounds 6 and 7.

Topics: Humans; Ligands; Loperamide; Molecular Structure; Morphine; Piperidines; Receptors, Opioid, mu; Structure-Activity Relationship

Although dopamine D(3) receptors have been associated with cocaine abuse, little is known about the consequences of chronic cocaine on functional activity of D(3) receptor-preferring compounds. This study examined the behavioral effects of D(3) receptor-selective 4-phenylpiperazines with differing in vitro functional profiles in adult male rhesus monkeys with a history of cocaine self-administration and controls. In vitro assays found that PG 619 (N-(3-hydroxy-4-(4-(2-methoxyphenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide HCl) was a potent D(3) antagonist in the mitogenesis assay, but a fully efficacious agonist in the adenylyl cyclase assay, NGB 2904 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-9H-fluorene-2-carboxamide HCl) was a selective D(3) antagonist, whereas CJB 090 (N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)-4-(pyridin-2-yl)benzamide HCl) exhibited a partial agonist profile in both in vitro assays. In behavioral studies, the D(3) preferential agonist quinpirole (0.03-1.0 mg/kg, i.v.) dose-dependently elicited yawns in both groups of monkeys. PG 619 and CJB 090 elicited yawns only in monkeys with an extensive history of cocaine, whereas NGB 2904 did not elicit yawns, but did antagonize quinpirole and PG 619-elicited yawning in cocaine-history monkeys. In another experiment, doses of PG 619 that elicited yawns did not alter response rates in monkeys self-administering cocaine (0.03-0.3 mg/kg per injection). Following saline extinction, cocaine (0.1 mg/kg) and quinpirole (0.1 mg/kg), but not PG 619 (0.1 mg/kg), reinstated cocaine-seeking behavior. When given before a cocaine prime, PG 619 decreased cocaine-elicited reinstatement. These findings suggest that (1) an incongruence between in vitro and in vivo assays, and (2) a history of cocaine self-administration can affect in vivo efficacy of D(3) receptor-preferring compounds PG 619 and CJB 090, which appear to be dependent on the behavioral assay.

Topics: Animals; Behavior, Animal; Cocaine; Conditioning, Operant; Dopamine Antagonists; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Fluorenes; Macaca mulatta; Male; Piperazines; Piperidines; Quinpirole; Receptors, Dopamine D3; Reinforcement, Psychology; Self Administration; Yawning

Modification of the partial dopamine type 2 receptor (D(2)) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D(2) antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D(2) in vitro, without displaying properties essential for interaction with D(2) in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D(2) antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D(2) antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The "agonist-like" kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D(2) antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique "dopaminergic stabilizer" characteristics, differentiating 12b from D(2) antagonists and partial D(2) agonists.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Binding, Competitive; Cell Line; Corpus Striatum; Dopamine; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Humans; Ligands; Male; Models, Chemical; Molecular Structure; Motor Activity; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

Syntheses of two 4-phenylpiperidines from bromobenzene have been developed involving anchoring to a fluorous-tag, Ir-catalysed borylation, Pd- and Co-catalysed elaboration then traceless cleavage. Although performed using 'cold' (i.e. unlabelled) bromobenzene as the starting material, these routes have been designed to minimise material loss via volatile intermediates and expedite purification during radiosynthesis from 'hot' (i.e. [(14)C] labelled) bromobenzene.

Topics: Boron; Bromobenzenes; Catalysis; Iridium; Isotopes; Piperidines; Radiochemistry; Volatilization

Various 4-phenylpiperidine-benzoxazin-3-ones were synthesized and biologically evaluated as urotensin-II (U-II) receptor antagonists. Compound 12i was identified from in vitro evaluation as a low nanomolar antagonist against both rat and human U-II receptors. This compound showed in vivo efficacy in reversing the ear-flush response induced by U-II in rats.

Topics: Animals; Benzoxazines; CHO Cells; Cricetinae; Cricetulus; Humans; Piperidines; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Urotensins

A nonlinear QSAR study was conducted on a series of 4-phenylpiperidine derivatives (4PPs) acting as mu opioid agonists by three-layer back-propagation neural network (NN) method. At first a variety of molecular descriptors were calculated and then selected with two-stage least squares combining partial least squares (PLS) method. The selected four molecular descriptors, out of 292 ones, were correlated with the known analgesic activities of 38 4PPs by NN method. The established QSAR model was further validated by five additional 4PPs, as an external testing set. Moreover, a pharmacophore model was hypothesized based on the results, which would be helpful for structural optimization of 4PPs.

Topics: Analgesics, Opioid; Drug Design; Least-Squares Analysis; Neural Networks, Computer; Piperidines; Quantitative Structure-Activity Relationship; Receptors, Opioid, mu

Differences in the anorectic activity of morphinan (e.g., naltrexone) and 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (4PP) opioid receptor antagonists have been described. In an attempt to explain these differences, the influence of Na(+) on opioid binding affinity and functional activity of 4PP antagonists was compared to other opioid antagonists. The binding affinities of neutral antagonists were unaffected by the addition of Na(+), whereas that for the peptide, inverse agonist N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH (ICI174864) was increased. Similarly, the binding affinities of the 4PP antagonist (3R,4R)-1-((S)-3-hydroxy-3-cyclohexylpropyl)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidine (LY255582) and other 4PP antagonists were increased in the presence of Na(+) with the greatest effects at the delta opioid receptor followed by the mu and kappa opioid receptors, respectively. Similar to ICI174864, 4PP antagonists were found to inhibit basal GTPgamma[(35)S] binding at the delta opioid receptor indicating inverse agonist activity. A correlation was observed between the binding affinities in the presence of Na(+), the inverse agonist potency, and the anorectic potency of 4PP antagonists. These data suggest that 4PP antagonists differ from morphinan antagonists in their inverse agonist activity and suggest a relationship between inverse agonism and anorectic activity.

Topics: Animals; Appetite Depressants; Binding, Competitive; Cell Membrane; CHO Cells; Cricetinae; Cyclohexanes; Diprenorphine; Dose-Response Relationship, Drug; Eating; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Guanosine 5'-O-(3-Thiotriphosphate); Ligands; Naltrexone; Narcotic Antagonists; Piperidines; Radioligand Assay; Rats; Rats, Zucker; Receptors, Opioid; Receptors, Opioid, delta; Sodium

Two series of compounds were recently reported as novel alpha1a-selective adrenoceptor antagonists. In the first series, a dihydropyrimidone moiety is attached to a 4-phenyl piperidine containing side chain, while in the second, it is linked to a 4-substituted phenyl piperazine containing side chain. These compounds having potential for the treatment of benign prostatic hyperplasia, a urological disorder in the older age male population, were subjected to a quantitative structure-activity relationship study. The analysis has helped to ascertain the role of different substituents in explaining the observed binding potencies of these analogues. In the first category of compounds, three sites R1, R2, and X were varied and from the quantitative structure-activity relationship, it emerged that X- and R1-substituents having respectively, the high values of field and resonance effects may lead to more potent alpha1a-antagonists. The substituent of R2, being either CH3 or C2H5, does not add to improve the activity and thus the site, at present, becomes redundant. This site may, however, be explored for some additional substituents in future. In the second series of compounds, the phenyl ring, linked to a piperazine moiety at the end of a side chain, was substituted with various groups onto different positions. From derived significant correlations, it appeared the less polar and/or bulky substituents at the meta- and para-positions and a more hydrophobic substituent at the para-position are advantageous.

Topics: Adrenergic Agonists; Adrenergic alpha-1 Receptor Antagonists; Binding Sites; Humans; Male; Piperazines; Piperidines; Prostatic Hyperplasia; Pyrimidinones; Quantitative Structure-Activity Relationship

This paper describes the synthesis of some conformationally restricted 4-phenylpiperidine analogues and their affinities for the guinea pig cerebellum sigma recognition site ([3H]-DTG) and the rat striatum dopamine D2 receptor ([3H]-(-)-sulpiride) in order to develop potent selective sigma ligands as tools in the investigation of this site in psychosis. It was found that both hexa- and octahydrobenz[f]isoquinolines with lipophilic N-substituents had high affinities for the sigma site. Notably, trans-3-cyclohexyl-1,2,3,4,4a,5,6,10b-octahydrobenz[f]isoquinoline (26) had an affinity of 0.25 nM making it the highest affinity sigma ligand reported to date. Moreover, it is at least 10,000-fold selective over the D2 receptor and could prove to be a valuable tool in the study of sigma sites. Other analogues such as 1H-indeno[2,1-c]pyridines and 1H-benzo[3,4]cyclohepta[1,2-c]pyridines also displayed high sigma site affinity.

Topics: Animals; Cerebellum; Chemical Phenomena; Chemistry, Physical; Guinea Pigs; Isoquinolines; Male; Molecular Conformation; Molecular Structure; Piperidines; Rats; Rats, Inbred Strains; Receptors, Dopamine; Receptors, Dopamine D2; Receptors, Opioid; Receptors, sigma; Structure-Activity Relationship; X-Ray Diffraction

sigma receptors may represent an exciting new approach for the development of novel psychotherapeutic agents. Unfortunately, many of the commonly used sigma ligands lack selectivity (e.g., many bind at phencyclidine or dopamine receptors) or suffer from other serious drawbacks. Recently, we described a series of 2-phenylaminoethanes that bind at sigma receptors with high affinity and selectivity. Because there is evidence that 1-phenylpiperazines can structurally mimic the 2-phenylaminoethane moiety, we prepared a series of 1-phenylpiperazines and related analogues and incorporated structural features already shown to enhance the sigma binding of the 2-phenylaminoethanes. Several of these derivatives bind at sigma receptors with high affinity (Ki = 1-10 nM) and lack appreciable affinity for phencyclidine and dopamine receptors. In as much as certain of these agents structurally resemble the high-affinity, but nonselective, sigma ligand haloperidol, and because they bind with 10 times the affinity of haloperidol, we have apparently identified what appears to be the primary sigma pharmacophore of that agent.

Topics: Animals; Guinea Pigs; In Vitro Techniques; Ligands; Piperazines; Piperidines; Radioligand Assay; Receptors, Dopamine; Receptors, Neurotransmitter; Receptors, Opioid; Receptors, Phencyclidine; Receptors, sigma; Structure-Activity Relationship

The 4-(m-OH-phenyl)piperidines are a flexible fragment of the morphine/benzomorphan fused-ring opioids. Analogs in this family were synthesized with varying 4-alkyl substituents increasing in bulk from H through methyl, n-propyl, to t-butyl, each with the three N-substituents methyl, allyl, and phenethyl. These twelve compounds were evaluated for analgetic agonism in mice using two different models for antinociceptive activity, acetic acid writhing and tail-flick, the latter by both subcutaneous and intracerebroventricular routes of administration. Antagonism to morphine analgesia was also measured by the mouse tail-flick procedure. Binding affinities of these new analogs to different opioid receptor subtypes were determined. Energy conformational calculations on these compounds were also carried out using the empirical energy program called MOLMEC, in order to better understand how the 4-R substituents modulate receptor binding affinities and efficacies. The results obtained show that, in general, the compounds studied are mu-selective and vary in agonist potency from weak to morphine-like. Significant differences in rank order of analgetic potencies and their relationship to receptor affinities were obtained from the results of subcutaneous and intracerebroventricular administration. Results of energy-conformational calculations for twelve N-methyl compounds indicate that those with 4-alkyl substituents favor a common, non-morphine-like phenyl axial conformation. The 4-t-butyl compounds are, in fact, the first simple mono-alkyl-substituted 4-phenyl-piperidines predicted to definitely exist in a phenyl axial conformation, as confirmed by X-ray analysis. On the basis of this common phenyl axial conformation, the observed variation in mu receptor affinities and efficacies of the 4-methyl, 4-n-propyl, and 4-t-butyl compounds could be understood and the behavior of 4-ethyl and 4-isopropyl analogs predicted. Two equatorial conformers (rotamers) were found to be the preferred forms of the analogs with 4-R being H or an ester group, or with a 3-methyl group added trans (beta) to the 4-R group. Taking into account the rotational flexibility of these analogs, these two conformers could be used to understand differences in high and low efficacy compounds observed among analogs with preferred phenyl equatorial conformations. None of the analogs exhibit a fused-ring-like N-substituent modulation of efficacy. This result can, perhaps, be understood by their inability

Topics: Analgesics; Animals; In Vitro Techniques; Injections, Intraventricular; Molecular Conformation; Morphine; Piperidines; Rats; Rats, Inbred Strains; Receptors, Opioid; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Structure-Activity Relationship

Topics: Animals; Central Nervous System Stimulants; Chemistry, Pharmaceutical; Mice; Pharmacology; Pharmacy; Piperidines; Rabbits; Research; Seizures; Spectrum Analysis

Topics: Central Nervous System; Chemistry, Pharmaceutical; Mice; Pharmacology; Pharmacy; Piperidines; Research; Seizures; Toxicology; Tremor

Topics: Analgesics; Analgesics, Non-Narcotic; Analgesics, Opioid; Antipyretics; Antitussive Agents; Piperidines

Topics: Analgesics; Meperidine; Piperidines

The analgesic potency of a series of new compounds related to pethidine has been measured in rats. The replacement of the methyl group on the nitrogen atom of pethidine by groups containing ether linkages produces an increase in potency. Two different positions for the oxygen atom are particularly beneficial, but the effects, in these two positions, appear to be exerted in different ways and are not additive. Simple toxicity tests in mice and rats and tests on respiration in rats of five of the more potent compounds revealed no unexpected adverse action.

Topics: Analgesics; Analgesics, Non-Narcotic; Animals; Antipyretics; Carboxylic Acids; Cell Respiration; Meperidine; Mice; Piperidines; Rats; Respiration

Topics: Acetophenones; Esters; Mannich Bases; Meperidine; Piperidines; Propiophenones

Topics: Analgesics; Carboxylic Acids; Meperidine; Piperidines

Topics: Humans; Piperidines

Topics: Humans; Meperidine; Piperidines; Stupor

Topics: Anesthesia, Local; Anesthetics; Anesthetics, Local; Humans; Piperidines

Topics: Carbonates; Diethyl Pyrocarbonate; Formates; Hydrogen Cyanide; Meperidine; Piperidines

Topics: Analgesics; Aspirin; Guinea Pigs; Meperidine; Morphine; Piperidines; Salicylates