Arthur Glenn Romero

Oxidative cyclization of acyclic ureas with bis(trifluoroacetoxy)iodobenzene to generate N-substituted 2-benzimidazolinones

Abstract A facile method to synthesize N-substituted 2-benzimidazolinones from secondary aromatic amines is presented. Sequential treatment of a secondary aromatic amine with phosgene and methoxylamine afforded an acyclic 3-substituted 3-aryl-1-methoxy urea. Brief exposure of this urea to bis(trifluoroacetoxy)iodobenzene induced an oxidative cyclization to the ortho-position of the benzene ring, resulting in the formation of a 3-substituted 1-methoxy-2-benzimidazloinone. Hydrogenation over Pd C cleaves the methoxy group to afford the N-substituted 2-benzimidazolinone.

Substituted 4-aminopiperidines having high in vitro affinity and selectivity for the cloned human dopamine D4 receptor

We have discovered two substituted 4-aminopiperidine compounds having high in vitro affinity and selectivity for the human dopamine D1 receptor. Both compounds, 3-ethoxy-N-methyl-N-[1-(phenylmethyl)-4-piperidinyl]-2-pyridinylamine (U-99363E), and its 3-isopropoxy analog (U-101958), were found through a routine receptor binding screen. The determined affinities (Ki) of these compounds for the cloned human dopamine D4 receptor were 2.2 and 1.4 nM, respectively. They exhibited at least 100-fold lower affinities for dopamine D2 and for other dopaminergic, serotonergic and adrenergic receptors. Both compounds were found to antagonize quinpirole-induced mitogenesis in Chinese hamster ovary cells expressing the human dopamine D4 receptor. In spite of their poor metabolic stability and low bioavailability. U-99363E and U-101958 appear to be among the first high-affinity, highly selective dopamine D4 receptor antagonists reported, and may have utility in in vitro investigations requiring selective tagging or blockade of dopamine D4 sites.

Synthesis of metabolically stable arylpiperazine 5-HT1A receptor agonists

Abstract Although N-alkylarylpiperazines as a class are finding use as anxiolytics and antidepressants, many of these arylpiperazines are highly metabolically labile at the n-alkyl-piperazine bond. We have found that cyclopropanating the n-butyl chain contained in the 5-HT1A receptor agonist ipsapirone (2) instills a resistance to this metabolism as well as providing information about the geometrical requirements of the 5-HT1A receptor.

Chapter 3. Advances in Central Serotoninergics

Publisher Summary The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in the etiology or treatment of so many medical problems, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, hypertension, stroke, migraine, and nausea. This chapter discusses the recent advancement in the research of serotonin. The 5-HT1 receptor is a high affinity binding site and is divided into four subgroups. In the central nervous system (CNS), the 5-HT1A receptor is broadly distributed, occurring as a somaldodendritic autoreceptor on 5-HT neurons. The 5-HT1A receptor has been widely implicated in anxiety and depression. The 8-OH-DPAT is the prototypical 5-HT1A agonist and in its radiolabeled form is used to characterize the 5-HT1A receptor. A growing body of evidence indicates that compounds in the arylpiperazine class have anxiolytic and antidepressant properties in humans. This effect is thought to be mediated by an inhibitory action on neurons and not simply a result of agonist induced hypothermia. Selective 5-HT1A antagonist remains elusive. While not selective, the most commonly used 5-HT1A antagonists are spiperone, propranolol, and pindolol. Although the 5-HT1B receptor is found in rats and mice, its presence has not been demonstrated in humans. Most agents that bind at the 5-HT1C receptor also bind at 5-HT2 receptors. Although it is not selective, ketanserin is the prototypical 5-HT2 receptor antagonist. There has been a longstanding interest in 5-HT2 antagonists for the prophylactic treatment of migraine. Despite the large amount of research aimed at discovering 5-HT3 receptor ligands, selective ligands have only recently become available. A large number of compounds have been prepared that bind at the 5-HT3 receptor as antagonists. Many of these compounds are clinically effective in reducing the nausea caused by radiation and chemotherapy cancer treatments.

An improved synthesis of the dopamine autoreceptor antagonist (+)-cis-8-methoxy-1-methyl-2-(dipropylamino)tetralin (AJ-76)

Abstract A new and efficient synthesis of (+)-cis-8-methoxy-1-methyl-2-(dipropylamino)tetralin, AJ-76, and its monopropyl analog, UH-232, was achieved. Relative stereochemistry was controlled by doubled bond hydrogenation, followed by enantiomeric resolution with quinine to obtain optically pure material. Overall, AJ-76 is synthesized in 9 percent overall yield, including the optical resolution.