Enantiomeric conformers of the opioid agonist ketobemidone HCl in the crystal state

A crystal of the potent opioid agonist ketobemidone [1-methyl-4-(3-hydroxyphenyl)-4-propionylpiperidine] HCl was analyzed by X-ray crystallography. The crystal was monoclinic, space group P2₁/n with four molecules in the unit cell. In agreement with MM2 calculations (J. Med. Chem. 25:1127–1133, 1982), the crystal contains mirror image conformers in which the phenyl ring is equatorial to the piperidine ring. The conformers are enantiomers since they are not superimposable. One conformer is predicted to be responsible for the typical morphine-like activity of the compound since it closely matches the preferred conformer of the morphine-like (+)-phenylmorphan whereas the other conformer resembles the preferred conformers of (+)-β-prodine and (?)-phenylmorphan which have atypical opioid properties and/or structure–activity relationships. The importance of considering the conformational enantiomers of a nonchiral receptor ligand in centrosymmetric crystal structures is emphasized. © 1993 Wiley-Liss, Inc.     

Absolute configuration and conformation of the pure opioid antagonist (+)-2,9 alpha-dimethyl-5-(m-hydroxyphenyl)morphan.

(+)-2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid kappa-receptors is greater than its affinity for opioid mu-receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X-ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (-)-phenylmorphan while the weak atypical agonist (-)-2,9 alpha-dimethyl-5-(m- hydroxyphenyl)morphan corresponds to the potent morphine-like (+)-phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2-87 and found to vary from that of the two parent compounds. The atypical properties of the two 9 alpha-methyl analogs is consistent with an opioid ligand model which proposes that morphine-like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X-ray crystallography and computed with the MM2-87 program.     

Interaction of (+)- and (-)-3-PPP with the dopamine receptor in the anterior pituitary gland

The interaction of the enantiomers of the novel dopamine agonist, 3-PPP (3-hydroxyphenyl)-N-n-piperidine) with the dopamine receptor in the anterior pituitary gland was examined. Both (+)- and (-)-3-PPP were effective in suppressing the elevation in serum prolactin (PRL) concentrations in rats treated with alpha-methyl-paratyrosine, an inhibitor of dopamine synthesis. The (+)-enantiomer was slightly more potent than the (-)-enantiomer in this regard. In addition, the secretion of PRL from anterior pituitary tissue under in vitro conditions was significantly inhibited by both isomers of 3-PPP, with (+)-3-PPP being approximately 10 times more potent than (-)-3-PPP. Both (+)- and (-)-3-PPP displaced 3H-(-)-N-n-propylnorapomorphine (3H-NPA) and 3H-spiperone from bovine anterior pituitary membranes. The Hill coefficients of (+)- and (-)-3-PPP for the displacement of 3H-spiperone were 0.6 and 0.7, respectively. These results are consistent with the view that the (+)- and (-)-enantiomer exhibit dopamine agonist effects at dopamine receptor sites in the anterior pituitary gland. However, (+)-3-PPP demonstrated marked differences in affinity for 3H-NPA- and 3H-spiperone labeled-sites, whereas (-)-)3-PPP showed the same order of affinity for these two sites. In view of these results and the fact that (-)-3-PPP has also been characterized as a dopamine antagonist at postsynaptic receptor sites in the striatum, (-)-3-PPP might be best described as a partial agonist at pituitary dopamine receptors. Moreover, these data are suggestive of a similarity, at least on a pharmacological basis, between dopamine autoreceptors and dopamine receptors in the anterior pituitary gland.     

Design,synthesis, and pharmacological evaluation of JDTic analogs to examine the significance of replacement of the 3-hydroxyphenyl group with pyridine or thiophene bioisosteres

The potent and selective KOR antagonist JDTic was derived from the N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine class of pure opioid antagonists. In previous studies we reported that compounds that did not have a hydroxyl on the 3-hydroxyphenyl group and did not have methyl groups at the 3- and 4-position of the piperidine ring were still potent and selective KOR antagonists. In this study we report JDTic analogs 2, 3a–b, 4a–b, and 5, where the 3-hydroxyphenyl ring has been replaced by a 2-, 3-, or 4-pyridyl or 3-thienyl group and do not have the 3-methyl or 3,4-dimethyl groups, remain potent and selective KOR antagonists. Of these, (3R)-7-hydroxy-N-(1S)-2-methyl-[4-methyl-4-pyridine-3-yl-carboxamide (3b) had the best overall binding potency and selectivity in a [³⁵S]GTPγS functional assay, with a K_e = 0.18 nM at the KOR and 273- and 16,700-fold selectivity for the KOR relative to the MOR and DOR, respectively. Calculated physiochemical properties for 3b suggest that it will cross the blood–brain barrier.     

Enantioselective syntheses and calcium channel modulating effects of (+)- and (−)-3-isopropyl 5-(4-methylphenethyl) 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylates

The (+)- and (?)-enantiomers of 3-isopropyl 5-(4-methylphenethyl) 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylate were synthesized using an efficient highly enantioselective (ee ≥ 96%) variant of the Hantzsch dihydropyridine synthesis. The key step in this procedure involved the asymmetric Michael addition of a metalated chiral aminocrotonate, derived from D -valine or L -valine, respectively, to the Knoevenagel acceptor (Z)-2-isopropoxycarbonyl-1-(2-pyridyl)-but-1-en-3-one. Both enantiomers exhibited a dual cardioselective partial calcium channel agonist (positive inotropic)/smooth muscle selective calcium channel antagonist effect. The relative in vitro smooth muscle calcium channel antagonist activities of the (?):(+) enantiomers was 26:1. In contrast, the (+)-enantiomer exhibited a greater in vitro positive inotropic effect on guinea pig left atrium where the contractile force was maximally increased by 14.8% at a concentration of 1.63 × 10^?8 M. © 1994 Wiley-Liss, Inc.     

Studies on the stereoselective effects of a novel 5-HT2 receptor antagonist on contractile responses of rat aorta

The effect of the enantiomers of a novel 5-HT2 receptor antagonist, (+/-)-(1R,3S)-1-[2-[4-[3-(p-fluorophenyl)-1-indanyl]-piperazinyl] ethyl]-2-imidazolidinone, was studied on serotonin (5-HT), noradrenaline (NA), potassium (K+), and calcium (Ca2+)-induced contractions in isolated rat thoracic aorta. The enantiomers shifted the 5-HT, NA, K+, and Ca2+ concentration-response curves to the right in a concentration-dependent manner and depressed the maximal contractile responses. The (+)-enantiomer was a far more potent inhibitor of 5-HT-induced contractions than the (-)-enantiomer. The (+)-enantiomer and phentolamine, both at 10(-6) M, had equal inhibitory effects on NA-evoked contractions. The (+)-enantiomer was again more potent inhibiting NA-induced contractions than the (-)-enantiomer. Both enantiomers had an equieffective inhibitory effect on K+ and Ca2(+)-induced contractions. The results show that the 5-HT and alpha-adrenoceptor antagonism of the two enantiomers is stereoselective, the (+)-enantiomer being more potent than the (-)-enantiomer. In contrast the enantiomers had equal, nonstereoselective inhibitory effects on K+ and Ca2(+)-evoked contractions.     

Chiral purity determination of tobacco alkaloids and nicotine-like compounds by 1H NMR spectroscopy in the presence of 1,1′-binaphthyl-2,2′-diylphosphoric acid

The enantiomeric purity of several tobacco alkaloids and nicotine-like compounds was determined using ¹H NMR (300 MHz) spectroscopy in the presence of (-)-(R)-1,1′binaphthyl-2,2′-diylphosphoric acid (BNPPA) as a chiral complexing agent. The most significant signal splitting resulting from diastereoisomeric complexation are seen for chemical shifts in the proximity of the pyridinyl nitrogen. Chemical shift data exclude any contribution of the pyrrolidinyl protons to chiral recognition, but when the pyrrolidine ring is replaced by a piperidine ring, i.e., for compounds such as rac-anabasine and rac-anatabine, non-equivalence between enantiomers was observed for protons close to the piperidine ring. A new approach for the preparation of the pure (-)-(S)-and (+)-(R)-enantiomers of nornicotine, a tobacco alkaloid and metabolite of nicotine, was developed. The optically pure enantiomers thus obtained were used to establish the minimum sensitivity of the NMR spectroscopic method of chiral analysis. These findings provide a new, general, and facile method for the determination of enantiomeric purity of tobacco alkaloids and nicotine-like compounds. © 1996 Wiley-Liss, Inc.     

Absolute configuration and biological activity of mequitamium iodide enantiomers

The enantiomers of 1-methyl-3-(10H-phenothiazine-10-ylmethyl)-1-azoniabicyclo[2,2,2]octane iodide ( 1 ) were prepared by chiral chromatographic resolution of the precursor mequitazine ( 2 ). The (+)-(S)-enantiomer 1b is 10-fold more potent than (?)-(R)-enantiomer 1a as a histamine antagonist, while the two enantiomers show the same antimuscarinic activity in vitro. The absolute configuration of the more active dextrorotatory isomer has been determined by X-ray analysis. Conformational analysis and molecular modeling suggest that the (+)-(S)-enantiomer can adopt a conformation similar to that attributed to the receptor binding conformers of classical antihistamines. © 1994 Wiley-Liss, Inc.     

Key structural features in cis-carane, (+)-3-carene,cis-pinane, (+)-α-pinene,and (−)-β-pinene influencing red turpentine beetle primary attraction when released with ethanol

1. In US Pacific Northwest ponderosa pine forests the primary attraction order shown previously for red turpentine beetle, Dendroctonus valens (Coleoptera: Curculionidae: Scolytinae), is (−)-β-pinene+ethanol > (+)-3-carene+ethanol > (+)-α-pinene+ethanol. The monoterpenes are bicyclic C₁₀H₁₆ isomers containing one 6-carbon ring with one double bond. Both pinenes have a 4-carbon second ring and differ only by their endocyclic or exocyclic double bond. The (+)-3-carene second ring has 3-carbons; its double bond is endocyclic like (+)-α-pinene.
2. Ring system and double bond influences on primary attraction were evaluated by hydrogenating (+)-3-carene and (+)-α-pinene to cis-carane and cis-pinane, respectively. Field test primary attraction strengths were (−)-β-pinene+ethanol > cis-carane+ethanol > cis-pinane+ethanol > ethanol.
3. In combination with ethanol (i) a double bond is not required in either ring system to attract D. valens, (ii) the cis-carane bicyclic 3, 6-carbon ring system provides stronger beetle attraction than the cis-pinane 4, 6-carbon bicyclic ring system, and likely structural basis for stronger (+)-3-carene attraction over (+)-α-pinene, (iii) adding an exocyclic double bond to the 4, 6-carbon ring system elevates attraction above the 3, 6-carbon ring system with no double bond, and (iv) the 4, 6-carbon ring system is a much stronger attractant with an exocyclic rather than endocyclic double bond.

     

Synthesis and structure-activity relationships of a new series of 2alpha-substituted trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine as mu-selective opioid antagonists

Structure-activity relationships at the 2alpha-position of the piperidine ring of the trans-4,5-dimethyl-4-(3-hydroxyphenyl)piperidine mu-opioid antagonist series were investigated. This study showed that only small linear alkyl groups (methyl, propyl) are tolerated at the 2alpha-position of the piperidine ring of this series.     

Conformational aspects of the actions of some piperidine dicarboxylic acids at excitatory amino acid receptors in the mammalian and amphibian spinal cord

A series of piperidine dicarboxylates (PDA) have been tested for excitatory amino acid agonist and antagonist activity and for synaptic depressant properties in the spinal cords of frogs and immature rats in vitro and of cats in vivo. The substances tested comprised (±)-cis-2,3-PDA, (±)-cis-2,4-PDA, (±)-cis-2,5-PDA, (±)-cis-2,6-PDA, (±)-trans-2,3-PDA, (±)-trans-2,3-PDA and both (+) and (–) forms ofcis-2,3-PDA. Peak excitatory amino acid agonist activity was observed with (±)-trans-2,3- and (±)-trans-2,4-PDA. Excitatory amino acid antagonism and synaptic depressant activity was observed only withcis-dicarboxylates, this activity being greatest in the 2,3-analogue. The agonist actions of piperidine dicarboxylates were effectively depressed by the specific NMDA receptor antagonist, (–)-2-amino-5-phosphonovalerate and, where tested, also byd--aminoadipate and low concentrations of Mg²⁺. It was concluded that the major part of these agonist actions were mediated by NMDA receptors. The main structural feature of the NMDA agonist actions of these substances was considered to be their close relationship to N-alkyl-aspartic and glutamic acid molecules, with thetrans arrangement of the respective 2,3- and 2,4-situated carboxyl groups promoting most effective interaction with the active sites of the NMDA receptor. (±)-Cis-2,3-PDA depressed excitatory responses induced by NMDA, kainate, quisqualate, (±)-trans-2,3-PDA and (±)-trans-2,4-PDA, or evoked by dorsal root stimulation. Both monosynaptic and polysynaptic excitation were susceptible to the depressant action of this substance. The (–) isomer ofcis-2,3-PDA carried both excitatory amino acid agonist and antagonist activity and also the synaptic depressant properties observed with the racemic form of this substance. The (+) isomer showed little pharmacological activity. It is proposed that the structure-activity features of these heterocyclic amino acids indicate some of the conformational requirements for interaction with physiological excitatory amino acid receptors.This paper is dedicated to Dr. Derek Richter on his seventy-fifth birthday.     

Toxicokinetics of a single intravenous dose of rac-propranolol versus optically pure propranolol in the rat

Conscious male Wistar SPF Riv:TOX rats were dosed intravenously with 2.5, 5, or 10 mg/kg rac-propranolol·HCl, or with 5 mg/kg of either (-)-(S)- or (+)-(R)-propranolol·HCl. Disposition of (-)-(S)- and (+)-(R)-propranolol after dosing of rac-propranolol was linear in the dose range examined. Total plasma clearance was not changed in animals dosed with the individual enantiomers compared to the animals that were dosed with rac-propranolol. However, for (-)-(S)-propranolol both volume of distribution and elimination half-life decreased, whereas for (+)-(R)-propranolol increases were observed for these characteristics, in animals dosed with the individual enantiomers. Our observations suggest that the (+)-(R)-enantiomer competes with (-)-(S)-propranolol for plasma protein binding sites, resulting in lower plasma protein binding of the (-)-(S)-enantiomer when the racemate is administered. From recent toxicological experiments, it was concluded that rac-propranolol is more toxic than the individual enantiomers in the rat, when dosed iv at the same total mass. It is concluded that the observed potentiation of toxic effects of propranolol enantiomers when administered as a racemate can at least partly be explained by a pharmacokinetic interaction. © 1995 Wiley-Liss, Inc.     

Synthesis and pharmacology of the enantiomers of UH301: Opposing interactions with 5-HT1A receptors

The (S)-enantiomer of 5-fluoro-8-hydroxy-2-(dipropylamino) tetralin [(S)- 2a; (S)-UH301] was the first reported 5-HT_1A receptor antagonist. We now give a full account on the synthetic effort leading to the preparation of the racemate and the enantiomers of 2a. The crystal and molecular structure of 2a · HBr has been determined by X-ray diffraction and the absolute configuration has been deduced using statistical tests of the crystallographic R values. The unit cell is tetragonal (P4₁2₁2) with a = b = 13.2235 (2), c = 39.560(1) Å and contains two crystallographically independent molecules in each asymmetric unit. The two solid state conformers differ in the conformation of the N-propyl groups. The pharmacological characterization of the enantiomers was done by use of in vivo biochemical and behavioural assays in rats. The (R)-enantiomer of 2a is a 5-HT_1A receptor agonist of low potency while (S)- 2a does not exhibit any agonist properties at 5-HT_1A receptors. As a consequence of the opposing effects of the enantiomers, the racemate, rac- 2a, does not produce any clear-cut effects in rats. The reduced efficacy of (S)- 2a as compared to the well known 5-HT_1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin ( 1; 8-OH-DPAT) may be due to the fluoro-substituent induced negative potential of the aromatic ring. Chirality 8:531–544, 1996. © 1997 Wiley-Liss, Inc.     

Synthesis of (+)-(R)- and (−)-(S)-5-hydroxy-2-methyl-2-dipropylaminotetralin: Effects on rat hippocampal output of 5-HT, 5-HIAA,and DOPAC as determined by in vivo microdialysis

Racemic 5-methoxy-2-methyl-2-dipropylaminotetralin ( 3 ) has been prepared by a short synthetic route, in which the N,N-dipropyliminium perchlorate of 5-methoxy-2-tetralone ( 4 ) is a key intermediate. Racemic 3 was resolved by crystallization of the corresponding diastereomeric di-p-toluoyltartrates. The enantiomeric excess (%ee) of the phenolic derivatives of (+)-(R)- and (?)-(S)-3 [(+)-(R)- and (?)-(S)-2] was determined by ¹HNMR spectroscopic analysis of the corresponding diastereomeric (?)-(R)-1,1′-binaphthyl-2,2′-diylphosphoric acid salts utilizing ¹³C satellites. X-ray crystallography established the absolute configuration of (?)-(S)-2 · HCl. The enantiomers of 2 were tested for hippocampal output of 5-hydroxytryptamine, 5-hydroxyindoleacetic acid, and dihydroxyphenylacetic acid in rats by use of in vivo microdialysis. The (?)-(S)-enantiomer appeared to affect 5-HT-turnover, whereas (+)-(R)- 2 was inactive. Results obtained provide support for the previously reported hypothesis that the inactivity of (?)-(S)- 2 at central DA receptors is caused by the steric bulk of the C(2)-methyl group. This makes it possible to define a “DA D2 receptor essential volume.” © 1993 Wiley-Liss, Inc.     

Preparative and analytical separation of the zopiclone enantiomers and determination of their affinity to the benzodiazepine receptor binding site

We report the preparative separation of rac-zopiclone using malic acid as the resolving agent. Furthermore, two different methods for the analytical determination of zopiclone enantiomers by HPLC on chiral stationary phases are described. The benzodiazepine receptor binding of the isolated enantiomers was investigated. Half-maximal inhibitory concentrations of (+)- and (?)-zopiclone were 21 or 1,130 nmol/liter, respectively, indicating a more than 50 times higher affinity of the (+)-enantiomer toward the receptor. © 1993 Wiley-Liss, Inc.     

Synthesis and fungicidal activity of enantiomerically pure (R)- and (S)-silicon-containing azole fungicides

Enantiomerically pure (R)- and (S)-1-(1H-1,2,4-triazol-1-yl)-2-(4-fluorophenyl)-3-trimethylsilylpropan-2-ol 1 were prepared via an enantioselective Grignard reaction. The absolute stereochemistry of 1 was determined by X-ray analysis. In a comparison of in vitro antifungal activities of the enantiomers, the (-)-enantiomer with the R-absolute configuration was far more potent than the (+)-enantiomer.     

Facilitation of GABA-induced depression with PCP and sigma receptor agonists was mediated through catecholaminergic pathways

The purpose of this experiment was to investigate the interactions of norepinephrine with PCP (phencyclidine) and sigma receptor agonists--modulated GABA (gamma aminobutyric acid) response in the cerebellum. Drugs were directly applied to a single cerebellar Purkinje neuron of urethane-anesthesitized rat through a multibarrel pipette. (+)PCMP [1-(-1-phenylcyclohexyl)-3-methyl piperidine], a PCP receptor agonist, and dexoxadrol, a sigma receptor agonist, significantly enhanced GABA induced inhibition. In norepinephrine-depleted animals, however, both (+)PCMP and dexoxadrol did not modulate GABA's effect. In conclusion, our findings indicated that the PCP/sigma-induced facilitation of GABA reactions were mediated through noradrenergic system in the cerebellum.     

Benzofuran- and furan-2-yl-(phenyl)-3-pyridylmethanols: Synthesis and inhibition of P450 aromatase

A series of benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives were prepared using an efficient 1-step procedure in good yields. In addition furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were also prepared to determine the effect of the benzene ring in benzofuran with respect to inhibitory activity. The pyridylmethanol derivatives were all evaluated in vitro for inhibitory activity against aromatase (P450_AROM, CYP19), using human placental microsomes. The benzofuran-2-yl-(phenyl)-3-pyridylmethanol derivatives showed good to moderate activity (IC₅₀=1.3–25.1?μM), which was either better than or comparable with aminoglutethimide (IC₅₀=18.5?μM) but lower than arimidex (IC₅₀=0.6?μM), with the 4-methoxyphenyl substituted derivative displaying optimum activity. Molecular modelling of the benzofuran-2-yl-(4-fluorophenyl)-3-pyridylmethanol derivative suggested activity to reside with the (S)-enantiomer. The furan-2-yl-(phenyl)-3-pyridylmethanol derivatives were devoid of activity indicating the essential role of the benzene ring of the benzofuran component for enzyme binding.     

Stereoselective degradation of benalaxyl in tomato, tobacco, sugar beet, capsicum, and soil

The stereoselective degradation of the racemic benalaxyl in vegetables such as tomato, tobacco, sugar beet, capsicum, and the soil has been investigated. The two enantiomers of benalaxyl in the matrix were extracted by organic solvent and determined by validated chiral high-performance liquid chromatography with a cellulose-tris-(3, 5-dimethylphenylcarbamate)-based chiral column. Rac-benalaxyl was fortified into the soil and foliar applied to vegetables. The assay method was linear over a range of concentrations (0.5-50 microg ml(-1)) and the mean recoveries in all the samples were more than 70% for the two enantiomers. The limit of detection for both enantiomers was 0.05 microg g(-1). The results in soil showed that R-(-)-enantiomer dissipated faster than S-(+)-enantiomer and the stereoselectivity might be caused by microorganisms. In tomato, tobacco, sugar, beet, and capsicum plants, there was significantly stereoselective metabolism. The preferential absorption and degradation of S-(+)-enantiomer resulted an enrichment of the R-(-)-enantiomer residue in all the vegetables.     

Preparation of milligrams of pure enantiomers using analytical-scale high-performance liquid chromatography

Pure enantiomers of an agrochemical process intermediate, (RS)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)-pentan-3-one ( 1 ), have been prepared on the milligram scale under overload chromatographic conditions on an analytical chiral column (250 × 4.6 mm i.d.). The effects of variation of temperature and mobile phase composition on retention factor, separation factor, and peak resolution have been investigated. Effects of flow rate, enantiomer ratio, sample concentration, and column load on productivity are also studied. Seven milligrams of the less retained (+)-enantiomer and 5 mg of the (?)-enantiomer were obtained from a single injection of 21 mg of (RS)- 1 . © 1994 Wiley-Liss, Inc.