Synthesis of 14C‐labeled piperidines and application to synthesis of [14C]SCH 351125, a CCR5 receptor antagonist

1‐Benzyl‐4‐hydroxy[2‐¹⁴C]piperidine, a useful intermediate in labeled compound synthesis, was prepared from [¹⁴C]formaldehyde in high yield. The distribution pattern of ¹⁴C in the product is consistent with a mechanism involving reversible iminium ion formation and rapid equilibration of the iminium ion through a cationic aza‐Cope rearrangement. These steps precede the rate‐determining intramolecular cyclization step. SCH 351125 is a potent, selective CCR5 receptor antagonist with potential as a treatment for HIV infection. [¹⁴C]SCH 351125, required for metabolism studies, was prepared from 1‐benzyl‐4‐hydroxy[2‐¹⁴C]piperidine in six steps. [¹⁴C]SCH 351125 is a mixture of four atropisomers. Preparation of [¹⁴C]SCH 351125 besylate salt of the desired atropisomer pair is also described. Copyright © 2007 John Wiley & Sons, Ltd.     

Multiple sites of action of ( +)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine (( +)-3PPP) in blood vessels

Functional effects of the σ ligand, (+)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3PPP), were explored in perfused rat tail and rabbit ear arteries in vitro. In the rat tail artery (+)-3PPP inhibited contractile responses to adrenergic nerve stimulation, an effect which was reversed to potentiation by the dopamine D₂ receptor antagonist sulpiride. In the rabbit ear artery, however, (+)-3PPP potentiated contractile responses to nerve stimulation, an effect which was unchanged by sulpiride. In the rat tail artery, blockade of norepinephrine uptake by cocaine and deoxycorticosterone in the presence of sulpiride revealed two additional actions of (+)-3PPP. First, an inhibitory action on the monoamine uptake site was confirmed by direct measurement of [³H]norepmephrine accumulation. Second, at higher concentrations, an action to inhibit contractile responses to adrenergic nerve stimulation was manifested at a still unidentified site. These studies demonstrate that the observed functional effect of (+)-3PPP results from its combined actions on three individual sites with the net effect dependent on the relative densities of these different receptor sites in each type of vessel.     

Biological activities of 3,4,5‐trihydroxypiperidines and their N‐ and O‐derivatives

3,4,5‐Trihydroxypiperidines belong to the family of 1,5‐dideoxy‐1,5‐iminosugar natural products and are structural analogues of pentose monosaccharides in the pyranose form. The biological activities of these apparently structurally simple molecules and their N‐ and O‐alkylated and ‐arylated derivatives are no less remarkable than their C‐6 hydroxymethyl counterparts of the hexoses (such as 1‐deoxynojirimycin, DNJ). Their biological profiles indicate that the hydroxymethyl branch is crucial to neither potency nor selectivity, with O‐alkylation demonstrated to produce exquisite selectivity extending beyond glycosidase inhibition, to immunosuppressant and antibacterial activities.     

Effects of L-lysine and its metabolites on pentylenetetrazol-induced seizures

Lysine and its metabolic intermediates were studied for their effect on pentylenetetrazol (PTZ)-induced seizures in mice. L-Lysine at dosages above 2 mmol/kg given i.p. significantly increased seizure protection and seizure latency (the time required to develop seizures after PTZ injection) with a peak effect dose at 10 mmol/kg. A pretreatment time of 15 min was required to significantly prolong seizure latency with a peak effect time of 45 min. D-Lysine at 10 mmol/kg i.p. afforded some seizure protection and significantly prolonged seizure latency but has a peak effect time of 15 min. When administered intracerebroventricularly, both L-lysine and piperidine at 0.1 mmol/kg prolonged seizure latency significantly, and increased seizure protection slightly. L-Pipecolic acid at the same dose given through the same route, however, shortened seizure latency significantly. L-alpha-Aminoadipic acid, on the other hand, had no significant effect. Lysine metabolites that prolonged seizure latency also increased seizure protection and decreased seizure death, and one that shortened seizure latency had the opposite effect. The anticonvulsant activity of lysine and its metabolites was explained on the basis of their connection with the GABAergic transmission.     

氮杂环类化合物的反应研究

目的本文对氮杂环类化合物的反应进行研究。方法 N-甲基六氢吡啶及托品酮与溴乙腈反应制得季胺盐溴化N-甲基-N-腈甲基六氢吡啶和溴化N-甲基-N-腈甲基托品酮,得到的季胺盐在四氢呋喃中与过量氢化钠反应。结果前者反应得到甲基转移的产物,后者发生Hofmann消除反应。结论溴化N-甲基-N-腈甲基六氢吡啶在氢化钠作用下,首先发生甲基转移反应,进而与四氢呋喃中的不纯物过氧化氢物产生的甲酸酯反应生成化合物2-六氢吡啶基-2-腈基-丙醛。阿托品化合物在氢化钠作用下是首先发生Hofmann消除反应,进而环合生成化合物3-氨基-1-甲基-2,7,8,8a-四氢-环庚吡咯-4-酮。     

Labeling in vivo of sigma receptors in mouse brain with [3H]-(+)-SKF 10,047: Effects of phencyclidine, (+)- and (−)-N-allylnormetazocine,and other drugs

The sigma receptor, so named because of the distinct pharmacolgical profile produced by its prototypic agonist SKF 10,047 (N-allynormetazocine), is believed to mediate mania and psychotomimetic effects in man. While this sigma receptor has received extensive biochemical and pharmacological characterization in vitro, little information is available on the nature of the sigma site in vivo. In the present study, we examined the binding of [³H]-(+)-SKF 10,047 to sigma receptors in mouse brain in vivo and to sigma receptors in mouse and guinea pig brain in vitro and determined the relative potencies of various drugs in displacing this ligand. Mice were injected with 5 μCi of [³H]-(+)-SKF 10,047 into the tail vein. After various time intervals, the mice were decapitated; their brains were rapidly removed, weighed, and homogenized in 50 mM Tris-HCI buffer, pH 7.7; and total and particulate bound radioactivity were determined. Specifically bound [³H]-(+)-SKF 10,047 in the particulate fraction was defined as the difference in total radioactivity in the particulate fraction obtained from vehicle-injected mice minus the radioactivity in the particulate fraction from haloperidol (2 mg/kg i.p.)-injected mice. Specifically bound [³H]-(+)-SKF 10,047 in the particulate fraction reached peak levels of 30 min after i.v. injection and constituted 90–95% of the total particulate radioactivity. Labeling of the sigma sites could be blocked in vivo by injecting mice i.p. with the drug 30 min before the i.v. injection of the ³H-ligand. Under these conditions, (+)-SKF 10,047, (+)-3-PPP, cyclazocine, pentazocine, and haloperidol were found to be the most potent compounds in reducing specific [³H]-(+)-SKF 10,047 binding. Neuroleptics such as thioridazine and chlorpromazine had good potency, while clozapine, spiperone, and sulpiride were very weak inhibitors in vivo. Specific [³H]-(+)-SKF 10,047 binding was also reduced in vivo by imipramine, dl-propranolol, bupropion, rimcazole, and phenoxybenzamine, but was not reduced by apomorphine and naloxone at doses of 50 mg/kg i.p. Phencyclidine, m-NH₂-PCP and (?)-3-PPP were only weak inhibitors of (+)-SKF 10,047 binding in vivo. The relative potencies of these agents obtained in vivo correspond well with their relative affinities obtained in vitro in mouse and guinea pig brain for displacing [³H]-(+)-SKF 10,047 but not with their relative affinities for displacing TCP in guinea pig brain. Comparison of the dose-response curves for the drug revealed the presence of perhaps two sites labeled by [³H]-(+)-SKF 10,047 in vivo.     

N-9-Fluorenylmethoxycarbonylpyroglutamate

Fmoc-glutamic acid is converted by thionyl chloride into the dichloride, which spontaneously cyclizes to Fmoc-pyroglutamyl chloride. The latter is stable to water. Pure Fmoc-pyroglutamyl chloride is obtained by washing the reaction mixture with water, which destroys uncyclized dichloride by converting it into the 2-alkoxy-5(4H)-oxazolone that is readily hydrolyzed. Fmoc-pyroglutamic acid and succinimidyl ester are obtained from the chloride by acid hydrolysis and reaction with N-hydroxysuccinimide, respectively.     

Anticonvulsant and proconvulsant properties of a series of structural isomers of piperidine dicarboxylic acid

Anticonvulsant and convulsant effects of various piperidine dicarboxylic acids have been evaluated following their intracerebroventricular (i.c.v.) or intraperitoneal (i.p.) injection in DBA/2 mice, a strain of mice genetically susceptible to sound-induced seizures.Protection against sound-induced seizures occurred after intraventricular administration of (±)cis-2,3-piperidine dicarboxylic acid (0.017–0.045 μmol), (±)trans-2,3-piperidine dicarboxylic acid (0.018–0.33 μmol) and (±)cis-2,4-piperidine dicarboxylic acid (0.57–1.68 μmol).Protection against sound-induced seizures occurred after intraperitoneal injection of (±)cis-2,3-piperidine dicarboxylic acid (0.52–1.8 mmol/kg).Myoclonus or convulsions occurred at various times after the intraventricular injection of cis-2,3-piperidine dicarboxylic acid, trans-2,3-, cis-2,4-, cis-2,5- and cis-2,6-, piperidine dicarboxylic acids, and after the intraperitoneal injection of trans-2,3-piperidine dicarboxylic acid. The latter effect was blocked by pretreatment with 2-amino-7-phosphonoheptanoic acid (0.33 mmol/kg, i.p.) a potent and specific antagonist of excitation induced by $\text{N-}\text{methyl-}\text{d}\text{-aspartate}$.The anticonvulsant action of cis-2,3-piperidine dicarboxylic acid and the convulsant action of trans-2,3-piperidine dicarboxylic acid were associated with predominant antagonist and agonist actions respectively, at receptors preferring $\text{N-}\text{methyl-}\text{d}\text{-aspartate}$.     

Pharmacological differentiation between responses of rat medullary dorsal horn neurons to noxious mechanical and noxious thermal cutaneous stimuli

Responses of lamina V medullary dorsal horn neurons to noxious thermal and noxious mechanical facial stimuli were challenged with iontophoretically appliedcis-2,3-piperidine dicarboxlic acid, a broad spectrum excitatory amino acid antagonist. This antagonist reduced neuronal responses to noxious mechanical stimuli but not responses to noxious thermal stimuli. These results suggest that different neural mechanisms underlie the responses of lamina V neurons to different noxious stimuli, and that responses to noxious mechanical stimuli appear to involve excitatory amino acid receptors.