Tominari Choshi

Nicotine blocks apomorphine‐induced disruption of prepulse inhibition of the acoustic startle in rats: possible involvement of central nicotinic α7 receptors

Nicotine has been reported to normalize deficits in auditory sensory gating in the cases of schizophrenia, suggesting an involvement of nicotinic acetylcholine receptors in attentional abnormalities. However, the mechanism remains unclear. The present study investigated the effects of nicotine on the disruption of prepulse inhibition (PPI) of the acoustic startle response induced by apomorphine or phencyclidine in rats. Over the dose range tested, nicotine (0.05–1 mg kg−1, s.c.) did not disrupt PPI. Neither methyllycaconitine (0.5–5 mg kg−1, s.c.), an α7 nicotinic receptor antagonist, nor dihydro‐β‐erythroidine (0.5–2 mg kg−1, s.c.), an α4β2 nicotinic receptor antagonist, had any effect on PPI. Nicotine (0.01–0.2 mg kg−1, s.c.) dose‐dependently reversed the disruption of PPI induced by apomorphine (1 mg kg−1, s.c.), but had no effect on the disruption of PPI induced by phencyclidine (2 mg kg−1, s.c.). The reversal of apomorphine‐induced PPI disruption by nicotine (0.2 mg kg−1) was eliminated by mecamylamine (1 mg kg−1, i.p.), but not by hexamethonium (10 mg kg−1, i.p.), indicating the involvement of central nicotinic receptors. The antagonistic action of nicotine on apomorphine‐induced PPI disruption was dose‐dependently blocked by methyllycaconitine (1 and 2 mg kg−1, s.c.). However, dihydro‐β‐erythroidine (1 and 2 mg kg−1, s.c.) had no effect. These results suggest that nicotine reverses the disruption of apomorphine‐induced PPI through central α7 nicotinic receptors.

A Novel Total Synthesis of Antibiotic Carbazole Alkaloid Carbazomycin G

Abstract A total synthesis of carbazomycin G ( 1 ) has been newly completed in seven steps. The 1,3-dioxygenated carbazole ( 4 ) via the 3-methoxy-1-methoxymethyloxycarbazole ( 11 ) as a synthetic precursor was synthesized by using the allene-mediated electrocyclic reaction of a 6π electron system generating from the 2 -propargylindole derivative ( 10 ), which was derived from the 3-vinylindole ( 8 ) in three steps. Finally, the oxidation of the phenol ( 4 ) followed by the addition of methyl lithium to the carbazole-1,4-quinone ( 3 ) provided carbazomycin G ( 1 ).

Total syntheses of carazostatin and hyellazole by allene-mediated electrocyclic reaction

Abstract The free radical scavenger carazostatin and the marine alkaloid hyellazole have been synthesized by a new type of allene-mediated electrocyclic reaction involving the indole 2,3-bond as a key step.

Progress towards the total synthesis of the bioactive calothrixins A and B

During the past decade, the total synthesis of calothrixin A and B, bioactive metabolites from cyanobacteria Calothrix sp., has been independently reported by six groups. Here, we describe the development of these synthetic efforts, including two biomimetic routes via indolo[2,3-a]carbazole.

Synthesis and antimalarial activity of calothrixins A and B, and their N-alkyl derivatives.

We synthesized calothrixin B using our developed biomimetic method and derived N-alkyl-calothrixins A and B. The in vitro antimalarial activity of the calothrixin derivatives, including calothrixins A and B, against the Plasmodium falciparum FCR-3 strain was evaluated. All test compounds exhibited antimalarial activity over a concentration range of 6.4×10(-6)-1.2×10(-7) M.

Effect of glutamate receptor antagonists on place aversion induced by naloxone in single-dose morphine-treated rats

1 The neurobiological mechanism underlying the negative motivational component of withdrawal from acute opiate dependence is far from understood. 2 Our objectives were to determine whether the glutamatergic system is involved in the motivational component of morphine withdrawal in acutely dependent rats and such an involvement is associated with dopaminergic neurotransmission. 3 We examined the effects of various kinds of glutamate receptor antagonists on conditioned place aversion (CPA) induced by naloxone‐precipitated withdrawal from a single morphine exposure 24 h before. Furthermore, the influence of pretreatment with the dopamine receptor antagonist haloperidol on those effects of glutamate receptor antagonists was also investigated. 4 CPA was attenuated in a dose‐dependent manner by all glutamate receptor antagonists examined including the NMDA receptor antagonists (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a,d]cyclo‐hepten‐5,10‐imine maleate (MK‐801) and phencyclidine hydrochloride (PCP), AMPA receptor antagonist 1‐(4‐aminophenyl)4‐methyl‐7,8‐methylenedioxy‐5H‐2,3‐benzodiazepine hydrochloride (GYKI 52466), and metabotropic receptor antagonists (±)‐2‐amino‐3‐phosphonopropionic acid (AP‐3) and (±)‐α‐methyl‐4‐carboxyphenylglycine (MCPG). The effects of MK‐801, GYKI 52466 and MCPG were blocked by haloperidol. 5 These results suggest that the glutamatergic system involving multiple classes of receptors plays a role in the motivational component of withdrawal from acute morphine dependence, and the function of the glutamatergic system would be closely associated with dopaminergic neurotransmission.

Total synthesis of bioactive indolo〔3,2-j〕phenanthridine alkaloid, calothrixin B

The total synthesis of bioactive calothrixin B (2) was completed which two kinds of carbazoles using three approaches. The common strategy was based on an allene-mediated electrocyclic reaction of a 6π-electron system involving one or two indole [b]-bonds for the construction of an appropriate 4-oxygenated 2,3,4-trisubstituted carbazole 28 or a 6-oxygenated 5-methylindolo[2,3-a]carbazole 39, respectively. Oxidation of the methyl group of 28 followed by reduction of the nitro group of 21 afforded the pentacyclic phenol 5, which was oxidized with CAN to give calothrixin B (2). In a biomimetic pathway, the fully protected 5-formylindolo[2,3-a]carbazole 40 with a methoxymethyl group provided calothrixin B (2) through N-methoxymethyl-calothrixin B 43.

The first total synthesis of the novel β-carboline alkaloid oxopropaline G

Abstract The first total synthesis of the new type of cytocydal β-carboline alkaloid oxopropaline G was achieved in 12 steps.

Ameliorating effects of tropisetron on dopaminergic disruption of prepulse inhibition via the α7 nicotinic acetylcholine receptor in Wistar rats

Nicotine has ameliorating effects on sensorimotor gating deficits in schizophrenia. We have shown that nicotine ameliorated disruption of prepulse inhibition (PPI) via the alpha(7) nicotinic acetylcholine receptor (nAChR) in Wistar rats. The 5-HT(3) receptor antagonist tropisetron was recently found to be an alpha(7) nAChR partial agonist. We initially investigated the effects of tropisetron on disruption of PPI induced by phencyclidine (PCP) (2mg/kg) or apomorphine (1mg/kg). Tropisetron had no effect on the disruption of PPI induced by PCP, but ameliorated the disruption by apomorphine. The ameliorating effect of tropisetron was antagonized by methyllycaconitine (2 or 5mg/kg), a partially selective alpha(7) nAChR antagonist. Next, to find the action site of tropisetron, we examined c-Fos protein expression in the nucleus accumbens (NAc), dorsolateral striatum (DLst) and ventral tegmental area (VTA). Tropisetron alone did not change the number of c-Fos-positive cells, whereas apomorphine increased the number of positive cells in the NAc and DLst. Tropisetron administration followed by apomorphine administration decreased the number of positive cells in the VTA compared with the apomorphine-alone group. These results suggest that tropisetron has an ameliorating effect on the sensorimotor gating deficits via the alpha(7) nAChR, and that one possible site of its action is the VTA.

A NEW SYNTHETIC ROUTE TO THE 1-OXYGENATED CARBAZOLE ALKALOIDS, MUKONINE AND CLAUSINE E (CLAUZOLINE I)

A new synthesis of the 1-oxygenated 1,3-disubstituted carbazole alkaloids, mukonine (la) and clausine (If) is described. The construction of the carbazole framework is based on an allene-mediated electrocyclic reaction involving the indole 2,3-bond. The 1,3-disubstituted 1-oxygenated carbazoles la and If are derived from the 1,2,3-trisubstituted carbazole.