Kenji Kihira

Bile alcohols function as the ligands of membrane-type bile acid-activated G protein-coupled receptor

TGR5 is a G protein-coupled receptor that is activated by bile acids, resulting in an increase in cAMP levels and the subsequent modulation of energy expenditure in brown adipose tissue and muscle. Therefore, the development of a TGR5-specific agonist could lead to the prevention and treatment of various metabolic disorders related to obesity. In the present study, we evaluated the ability of bile alcohols, which are structurally and physiologically similar to bile acids and are produced as the end products of cholesterol catabolism in evolutionarily primitive vertebrates, to act as TGR5 agonists. In a cell-based reporter assay and a cAMP production assay performed in vitro, most bile alcohols with a side chain containing hydroxyl group(s) were highly efficacious agonists for TGR5 comparable to its most potent ligand in the naturally occurring bile acid, lithocholic acid. However, the abilities of the bile alcohols to activate TGR5 varied with the position and number of the hydroxyl substituent in the side chain. Additionally, the conformation of the steroidal nucleus of bile alcohols is also important for its activity as a TGR5 agonist. Thus, we have provided new insights into the structure-activity relationships of bile alcohols as TGR5 agonists.

Chronic inhibition of the norepinephrine transporter in the brain participates in seizure sensitization to cocaine and local anesthetics

The involvement of chronic inhibition of monoamine transporters (MAT) in the brain with respect to sensitization to cocaine- and local anesthetic-induced seizures was studied in mice. Repeated administration of subconvulsive doses of meprylcaine as well as cocaine, both of which inhibit MAT, but not lidocaine, which does not inhibit MAT, increased seizure activity and produced sensitization to other local anesthetics. The effects of five daily treatments of monoamine transporter inhibitors on lidocaine-induced convulsions were examined 2 or 3 days after the last dose of the inhibitors. Daily treatments of GBR 12935, a specific inhibitor of dopamine uptake, significantly increased the incidence and the intensity of lidocaine-induced convulsions at 20 mg/kg and decreased the threshold of the convulsions. Daily treatments of desipramine and maprotiline, selective norepinephrine uptake inhibitors, markedly increased the incidence and intensity of lidocaine-induced convulsions, and decreased the threshold in a dose-dependent manner at between 5 and 20 mg/kg. Daily treatments of citalopram, a selective serotonin uptake inhibitor, at 10 and 20 mg/kg, produced no significant increase in the incidence or intensity of lidocaine-induced convulsions, but decreased the threshold of the convulsions. These results suggest that the chronic intermittent inhibition of monoamine uptake increases susceptibility to cocaine- and local anesthetic-induced seizures, and the norepinephrine transporter is an integral component of this sensitization.

Amnesic effects of the anticholinergic drugs, trihexyphenidyl and biperiden: differences in binding properties to the brain muscarinic receptor

An amnesic effect of anticholinergic drugs was previously described from several behavioral studies. We examined this effect induced by trihexyphenidyl and biperiden, clinically used in the parkinsonism and schizophrenic patients, by using passive avoidance tasks. Both of these drugs (0.1-10 mg/kg, s.c.) showed dose-dependent amnesic effects in the acquisition and retrieval phases. However, the effect induced by trihexyphenidyl was transient, whereas that of biperiden was long-lasting. To clarify the reason for the different duration of the amnesic activity, binding to the muscarinic receptor was examined. In the Scatchard analysis, trihexyphenidyl competed with [(3)H]quinuclidinyl benzilate ([(3)H]QNB) on the muscarinic receptor (showed increased K(d) and unchanged B(max) value), while biperiden decreased [(3)H]QNB binding (B(max) value) significantly. Furthermore, in an exchange assay for receptor inactivation, trihexyphenidyl binding to muscarinic receptors was exchanged by [(3)H]QNB completely, but biperiden decreased the exchangeable binding of [(3)H]QNB in a dose dependent manner (0.1-100 nM). These results suggested that the binding of trihexyphenidyl and biperiden to muscarinic receptor might be completely reversible and partially irreversible, respectively, whereas the K(i) values of these two drugs were similar. In conclusion, this difference in binding property may explain the difference in the time-course of the amnesic effect induced by trihexyphenidyl and biperiden.

Identification of (23S)-5β-cholestane-3α,7α,12α,23,25-pentol in cerebrotendinous xanthomatosis1,2

The synthesis of (23R)- and (23S)-5β-cholestane-3α,7α, 12α,23,25-pentols is described. Norcholyl aldehyde was converted into the cholestanepentols by a Reformatsky reaction with ethyl bromoacetate followed by a Grignard reaction with methylmagnesium iodide. One of the synthetic pentols, the 23S epimer was identical with a bile alcohol isolated from patients with cerebrotendinous xanthomatosis.

Daily cost of ophthalmic solutions for treating glaucoma in Japan

PURPOSE We conducted a study of the daily cost of various ophthalmic solutions used in Japan for treating glaucoma: beta-adrenergic blockers (11 products), epinephrine (3), cholinergics (3), prostaglandins (2), and carbonic anhydrase inhibitors (2). METHODS The total number of drops in one bottle of each solution was counted drop by drop. The cost per drop was calculated by dividing the government-controlled standard prices by the total number of drops in one bottle. The daily cost of therapy was calculated by multiplying the cost per drop by the number of drops typically used per day. RESULTS The average cost of each preparation was calculated based on the prices and the daily usage. The daily cost of the beta-adrenergic blockers studied ranged widely, from

Inhibition of serotonin transporters by cocaine and meprylcaine through 5-TH2C receptor stimulation facilitates their seizure activities.

0.43 to

Structure–activity relationship of bile alcohols as human farnesoid X receptor agonist

1.04. CONCLUSIONS These data may be useful in selecting ophthalmic products for glaucoma therapy in Japan.

Daily cost of ophthalmic solutions used to treat allergic conjunctivitis in Japan.

The present study examined whether the inhibition of serotonin transporters (SERT) contributes to cocaine- and other local anesthetics-induced convulsions, and which subtypes of 5-HT receptor are involved in the convulsions. For this purpose, cocaine, meprylcaine and lidocaine, all of which have different effects on SERT, were used as convulsants and the effects of serotonin reuptake inhibitors (SSRIs), specific agonists and antagonists for 5-HT receptor subtypes were evaluated in mice. Administration of SSRI, zimelidine, citalopram and fluoxetine, 5-HT(2A,2C) receptor agonist, R(-)-DOI and the 5-HT2C receptor agonists, mCPP, and MK212 resulted in a marked increase in incidence of convulsions and a reduction in the threshold of lidocaine-induced convulsions, while the 5-HT2B receptor agonist, BW723C86, had little influence. On the other hand, SSRI did not affect the measured parameters in meprylcaine- and cocaine-induced convulsions. R(-)-DOI, mCPP, and MK212 reduced the threshold of meprylcaine or cocaine with less extent than the reduction of lidocaine threshold. Incidence of cocaine- and meprylcaine-induced convulsions was significantly reduced by 5-HT(2A,2B,2C) antagonist, LY-53857, and 5-HT2C antagonist, RS 102221. The threshold of cocaine and meprylcaine was significantly increased by both antagonists. 5-HT2A antagonists MDL 11,939 and ketanserin, and 5-HT2B antagonist SB 204741 except at high doses had little effect on cocaine- and meprylcaine-induced convulsions. None of these antagonists altered the parameters of lidocaine-induced convulsions. Pretreatment with fluoxetine but not citalopram increased the plasma concentration of lidocaine. These results suggest that the increase of serotonergic neuronal activity through 5-HT2C receptor stimulation was responsible for increased activity of local anesthetics-induced convulsions and support the involvement of this mechanism in cocaine- and meprylcaine- but not in lidocaine-induced convulsions through their direct inhibitory action on central SERT.

Measurement of serum bile alcohol levels in liver dysfunction, using isotope dilution-mass spectrometry.

FXR (farnesoid X receptor) is a bile acid-activated nuclear receptor that regulates not only the biosynthesis and enterohepatic circulation of bile acids, but also triglyceride, cholesterol and glucose metabolism. FXR-mediated signaling pathways have become promising novel drug targets for the treatment of common metabolic and hepatic diseases. With the aim of uncovering novel modulators of FXR and further elucidating the molecular basis of FXR activation, we investigated the structure-activity relationships of a variety of naturally occurring sterols structurally related to bile acids in terms of their FXR agonist activity. Here, we report that the ability of bile alcohols to activate FXR varied with the position and number of hydroxyl groups existing in the steroid side chain of bile alcohols. In addition, we showed that the shortening of the steroid side chain of bile acids as well as bile alcohols resulted in a decline of the ability of these agents to activate FXR. Thus, we provide new insights into the structure-activity relationships of bile acids and bile alcohols as FXR agonists.

Urinary bile alcohols in liver dysfunction

PURPOSE To estimate the daily cost of various ophthalmic solutions used in Japan for treating allergic conjunctivitis, including nine anti-allergic drugs and six anti-inflammatory drugs. METHODS The drops contained in one bottle of each solution were counted. The cost per drop was calculated by dividing the government-controlled standard prices by the total number of drops in one bottle, and the daily cost of therapy was calculated by multiplying the cost per drop by the number of drops to be given per day. RESULTS The total number of drops of the anti-allergic drugs in a bottle ranged from 108 to 169 and that of the anti-inflammatory drugs from 100 to 145. The information in the package insert for these solutions recommends application 2–4 times daily. The price of the antiallergic drugs studied ranged from