N-pentyl Chain Research Articles

Impact of conformational and solubility properties on psycho-activity of cannabidiol (CBD) and tetrahydrocannabinol (THC)

Cannabidiol (CBD) is one among many others identified bioactive cannabinoid derivatives. It is the main component in Cannabis sativum oil and can be applied as potential therapeutic agent. It has not any psychoactive effects such as those caused by tetrahydrocannabinol (THC). The basic difference between CBD and THC is an opened or closed heterocycle ring. A conformational study using quantum chemical calculations was performed to the DFT/B3LYP/6-31G(d,p) level. The high energy barrier values, superior to 20 kcal/ mol, may explain the small ability of the CBD to exhibit psychostimulant effect. This property is controlled by steric hindrance between polar groups and nonpolar moieties. n-Pentyl chain has little influence on conformation of CBD. The conformational search by using a simplified cannabidiol derivative showed that stereo-electronic repulsions are responsible for the limitation on CBD conformations. CBD and THC have the highest lipophilicity values when compared to other agents on central nervous system.

Procedure for setting control for the turnover of new, potentially hazardous psychoactive substances. Detection of metabolites of a new APINAC psychoactive compound in rat urine by gas and liquid chromatography with mass spectrometry detection

The appearance of a new APINAC compound (AKB-57, ACBL(N)-018, adamantan-1-yl-1-pentyl-1H-indazol-3-carboxylate) in the Russian market of psychoactive drugs led to the need in setting measures of state control over its turnover and in solving the problem of categorizing this compound as a potentially hazardous psychoactive substance. To establish these control measures, it was necessary to determine the appropriate chromatographic–mass spectrometric characteristics and to search for its metabolites for their subsequent automated detection. The structure of an APINAC molecule has significant similarity with the molecules of other synthetic cannabinoids. In this paper, primary information on the metabolism of APINAC in the body of rats is presented. A number of putative metabolites, which are the products of hydrolysis of the initial structure and additional monohydroxylation of these products, carbonylation and carboxylation of the lateral N-pentyl chain of indazole-containing metabolites, were detected in rat urine by liquid chromatography–mass spectrometry in the mode of measurement of exact masses and gas chromatography–mass spectrometry. It was found that the formation of glucuronides is characteristic for 1-adamantol and its monohydroxylated metabolite and for the indazole-containing product of hydrolysis of APINAC. The presented mass spectra and retention characteristics of the detected metabolites can help in the detection of these (or similar) compounds in human urine.

In vitro and in vivo pharmacokinetics and metabolism of synthetic cannabinoids CUMYL-PICA and 5F-CUMYL-PICA

CUMYL-PICA [1-pentyl-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] and 5F-CUMYL-PICA [1-(5-fluoropentyl)-N-(2-phenylpropan-2-yl)-1H-indole-3-carboxamide] are recently identified recreationally used/abused synthetic cannabinoids, but have uncharacterized pharmacokinetic profiles and metabolic processes. This study characterized clearance and metabolism of these compounds by human and rat liver microsomes and hepatocytes, and then compared these parameters with in vivo rat plasma and urine sampling. It also evaluated hypothermia, a characteristic cannabimimetic effect. Incubation of CUMYL-PICA and 5F-CUMYL-PICA with rat and human liver microsomes suggested rapid metabolic clearance, but in vivo metabolism was prolonged, such that parent compounds remained detectable in rat plasma 24 h post-dosing. At 3 mg/kg (intraperitoneally), both compounds produced moderate hypothermic effects. Twenty-eight metabolites were tentatively identified for CUMYL-PICA and, coincidentally, 28 metabolites for 5F-CUMYL-PICA, primarily consisting of phase I oxidative transformations and phase II glucuronidation. The primary metabolic pathways for both compounds resulted in the formation of identical metabolites following terminal hydroxylation or dealkylation of the N-pentyl chain for CUMYL-PICA or of the 5-fluoropentyl chain for 5F-CUMYL-PICA. These data provide evidence that in vivo elimination of CUMYL-PICA, 5F-CUMYL-PICA and other synthetic cannabinoids is delayed compared to in vitro modeling, possibly due to sequestration into adipose tissue. Additionally, the present data underscore the need for careful selection of metabolites as analytical targets to distinguish between closely related synthetic cannabinoids in forensic settings.

High-Resolution Mass Spectrometry for Characterizing the Metabolism of Synthetic Cannabinoid THJ-018 and Its 5-Fluoro Analog THJ-2201 after Incubation in Human Hepatocytes.

Despite increasing prevalence of novel psychoactive substances, no human metabolism data are currently available, complicating laboratory documentation of intake in urine samples and assessment of the drugs' pharmacodynamic, pharmacokinetic, and toxicological properties. In 2014, THJ-018 and THJ-2201, synthetic cannabinoid indazole analogs of JWH-018 and AM-2201, were identified, with the National Forensic Laboratory Information System containing 220 THJ-2201 reports. Because of numerous adverse events, the Drug Enforcement Administration listed THJ-2201 as Schedule I in January 2015. We used high-resolution mass spectrometry (HR-MS) (TripleTOF 5600(+)) to identify optimal metabolite markers after incubating 10 μmol/L THJ-018 and THJ-2201 in human hepatocytes for 3 h. Data were acquired via full scan and information-dependent acquisition triggered product ion scans with mass defect filter. In silico metabolite predictions were performed with MetaSite and compared with metabolites identified in human hepatocytes. Thirteen THJ-018 metabolites were detected, with the major metabolic pathways being hydroxylation on the N-pentyl chain and further oxidation or glucuronidation. For THJ-2201, 27 metabolites were observed, predominantly oxidative defluorination plus subsequent carboxylation or glucuronidation, and glucuronidation of hydroxylated metabolites. Dihydrodiol formation on the naphthalene moiety was observed for both compounds. MetaSite prediction matched well with THJ-018 hepatocyte metabolites but underestimated THJ-2201 oxidative defluorination. With HR-MS for data acquisition and processing, we characterized THJ-018 and THJ-2201 metabolism in human hepatocytes and suggest appropriate markers for laboratories to identify THJ-018 and THJ-2201 intake and link observed adverse events to these new synthetic cannabinoids.

Synthetic cannabimimetic agents metabolized by carboxylesterases.

Synthetic cannabimimetic agents are a large group of diverse compounds which act as agonists at cannabinoid receptors. Since 2004, synthetic cannabinoids have been used recreationally, although several of the compounds have been shown to cause severe toxicity in humans. In this study, the metabolism of two indazole carboxamide derivatives, AB-PINACA and AB-FUBINACA, was investigated by using human liver microsomes (HLM). For both compounds, a major metabolic pathway was the enzymatic hydrolysis of the primary amide, resulting in the major metabolites AB-PINACA-COOH and AB-FUBINACA-COOH. Other major metabolic pathways were mono-hydroxylation of the N-pentyl chain in AB-PINACA and mono-hydroxylation of the 1-amino-3-methyl-1-oxobutane moiety in AB-FUBINACA. To identify the enzyme(s) responsible for the amide hydrolysis, incubations with recombinant carboxylesterases and human serum, as well as inhibition studies in HLM and human pulmonary microsomes (HPM) were performed. Carboxylesterase 1 (CES1) was identified as the major human hepatic and pulmonary enzyme responsible for the amide hydrolysis.We employed similar studies to identify the esterase(s) involved in the previously described hydrolytic metabolism of two quinolineindole synthetic cannabinoids, PB-22 and 5F-PB-22, as well as the closely related compound, BB-22. Our investigations again revealed CES1 to be the key enzyme catalyzing these reactions. The identified major metabolites of AB-PINACA and AB-FUBINACA are likely to be useful in documenting drug usage in forensic and clinical screening. Additionally, the identification of CES1 as the main enzyme hydrolyzing these compounds improves our knowledge in the emerging field of xenobiotic metabolism by esterases.

Detection and tentative identification of urinary phase I metabolites of phenylacetylindole cannabimimetics JWH-203 and JWH-251, by GC–MS and LC–MS/MS

The synthetic phenylacetylindole cannabimimetics, JWH-203 and JWH-251, have been identified in 'herbal' smoking mixtures following the widespread legislative control of 'first generation' compounds such as JWH-018 and CP47, 497(C8). N-Alkylindole cannabimimetics (including phenylacetylindoles) undergo extensive metabolism and little or none of the parent compounds are found in urine. Utilizing GC-MS and LC-MS/MS, a series of JWH-203 and JWH-251 urinary metabolites have been tentatively identified. These are products of mono- and dihydroxylation, monohydroxylation combined with formation of carbonyl group on the N-pentyl chain, carboxylation of N-pentyl chain and N-dealkylation combined with monohydroxylation. Additionally, trihydroxylated metabolites were detected for JWH-203. No parent compounds were detected. The monohydroxylated metabolites with the hydroxyl group positioned on the N-pentyl chain were the most abundant and were found to be suitable for establishing ingestion of JWH-203 or JWH-250. Maximum urinary concentrations of chain-monohydroxylated metabolites were observed at 2.5-3h (JWH-203) and 6-10h (JWH-251) following ingestion. These metabolites were observed (GC-MS) for to 10 and 8 days (JWH-203 and JWH-251, respectively).

2-(4-Methoxyphenyl)-1-pentyl-4,5-diphenyl-1H-imidazole

The title compound, C27H28N2O, is a lophine (2,4,5-triphenyl-1H-imidazole) derivative with an n-pentyl chain on the amine N atom and a 4-meth­oxy substituent on the benzene ring. The two phenyl and meth­oxy­benzene rings are inclined to the imidazole ring at angles of 25.32 (7), 76.79 (5) and 35.42 (7)°, respectively, while the meth­oxy substituent lies close to the plane of its benzene ring, with a maximum deviation of 0.126 (3) Å for the meth­oxy C atom. In the crystal, inversion dimers linked by pairs of C—H⋯O hydrogen bonds generate R 2 2(22) loops. These dimers are stacked along the a-axis direction.

The Identification of the Urinary Metabolites of 3-(4-Methoxybenzoyl)-1-Pentylindole (RCS-4), a Novel Cannabimimetic, by Gas Chromatography-Mass Spectrometry

3-(4-Methoxybenzoyl)-1-pentylindole (RCS-4), a synthetic indole-derived cannabimimetic, was first reported to the European Monitoring Centre for Drugs and Drug Addiction via the Early Warning System by Hungarian authorities in 2010 and later identified in head shop test purchases in Ireland. Using gas chromatography-mass spectrometry, we have identified a series of RCS-4 metabolites in urine samples from individuals admitted to hospitals with symptoms of drug intoxication. The metabolites were tentatively identified as products of (i) aromatic monohydroxylation; (ii) dihydroxylation; (iii) aromatic hydroxylation/oxidation of the N-pentyl chain to a ketone; (iv) O-demethylation; (v) O-demethylation/monohydroxylation of N-pentyl chain; (vi) O-demethylation/oxidation of the N-pentyl chain to a ketone; (vii) O-demethylation/aromatic hydroxylation/oxidation of the N-pentyl chain to a ketone; (viii) N-depentylation/aromatic monohydroxylation; and (ix) N and O-dealkylation. The parent compound was not detected. The O-demethylated metabolites were found to be the most useful metabolic markers for the identification of RCS-4 ingestion.

Arene-perfluoroarene interactions in crystal engineering: structural preferences in polyfluorinated tolans

The compounds 4-ROC6F4CCPh (4) where R = Me (a), Et (b), Prn (c), Pri (d), Bun (e), n-C5H11 (f), PhCH2 (g), PhCH2CH2 (h), 4-MeC6H4 (i), 4-EtC6H4 (j) and menthyl (k), have been prepared by reaction of C6F5CCPh (3) with ROH in the presence of KOH, and characterised by NMR (1H, 13C, 19F) and mass spectroscopy. The single-crystal structures of PhCCPh·C6F5CCC6F5 (1∶2), 3 and 4a,c,d,f,g,i have been determined by X-ray diffraction at 120–160 K, and that of 3 also calculated by an ab initio pseudo-potential DFT method. The tolan moiety is nearly planar in each molecule except 4a, which has a Ph/C6F5 dihedral angle of 25.8°. The R group adopts an out-of-plane orientation except in 4f, where the n-pentyl chain is nearly coplanar with the C6F5 group at the cost of severe distortion of the C(ar)–C(ar)–O angles (which differ by 13.5°). The structures of 1∶2, 3 (pseudo-isomorphous with 1∶2), 4a, 4g (disordered) and 4i contain stacks of alternating arene and perfluoroarene moieties; 4c and 4d form discrete centrosymmetric dimers with arene/perfluoroarene overlap, while 4f forms infinite stacks without such overlap. Differential thermal analysis and transmitted polarised light microscopy revealed no liquid-crystalline behaviour of 3 and 4.

The Synthesis of N-Vanillyl-arachidonoyl-amide (Arvanil) and its Analogs: An Improved Procedure for the Synthesis of the Key Synthon Methyl 14-Hydroxy-(all- cis)-5,8,11-tetradecatrienoate

Several arvanil analogs were synthesized where the end n-pentyl chain was branched and carried substituents at the terminal end of the chain. A high yielding total synthesis of these analogs was developed from methyl hex-5-ynoate, which was converted to the synthon 6 in a facile five step sequence (overall yield, 33%). The pharmacological profile of these novel analogs suggests that they may be acting through a novel site of action for anandamide (arachidonylethanolamide, AEA).

Molecular Properties of Pentyl-Cyano Mesogens Having Different Core Structures

Abstract The molecular properties of polarizability, polarizability anisotropy and dipole moment have been measured for a series of mesogenic molecules having a terminal cyano group and a terminal n-pentyl chain. Molecules investigated were of the form n-pentyl-X-cyano, where X was biphenyl, cyclohexyl-phenyl, phenyl-cyclohexyl, bicyclohexyl and bicyclo-octyl-phenyl. Measured polarizabilities were compared with bond additivity calculations for the molecules having different alkyl chain conformations. The relative nematic stabilities of the mesogens and their physical properties are discussed in terms of their measured molecular properties.

13C chemical shifts and spin-lattice relaxation in the nematic liquid crystal 4-cyano-4′-n-pentylbiphenyl

The 13C chemical shifts and spin-lattice relaxation times were obtained for all the resolved resonances in the isotropic and nematic phases of 5CB. NOE measurements were also obtained for the isotropic phase. A study of these data indicates that a flexibility gradient exists along the n-pentyl chain and that D⊥, the rotational diffusion constant for the entire molecule, can be estimated. A study of the chemical shifts of 5CB shows that a single average shielding tensor is inadequate for a proper description of the chemical shifts of this liquid crystal molecule. These results are compared with those previously obtained for MBBA and PAA.