The Disposition of (R)-α-Methylhistamine,a Histamine H3-Receptor Agonist,in Rats

Abstract— Using a modified HPLC method with a fluorescence spectrophotometer and a weak cation exchanger, it was possible to separate (R)-α-methylhistamine (α-methylhistamine) from histamine in plasma and various tissues. The assay was used to study the disposition and pharmacokinetic analysis of α-methylhistamine after a bolus intravenous administration to rats. After rapid intravenous administration (12·6 mg kg^?1), the plasma concentration declined biexponentially with a half-life of 1·3 min in the elimination phase. The area under the plasma concentration-time curve and total body clearance were 130 μg min mL^?1 and 97 mL min^?1 kg^?1, respectively. After administration, α-methylhistamine was immediately transferred to various tissues. The concentration was high in the kidney, lung, and liver (kidney > lung > liver), but low in the brain. The tissue-to-plasma concentration ratios in peripheral tissues were greater than 1, suggesting that the transfer of α-methylhistamine to peripheral tissues was due to a specialized transport mechanism or possibly to tissue binding. However, the finding that the tissue/plasma ratio in the brain was lower than unity suggests that the transport system in this tissue depends on a concentration gradient, and that α-methylhistamine crosses the blood-brain barrier in rats with difficulty.     

Synthesis of Potent Non-imidazole Histamine H3-Receptor Antagonists

Histamine has been converted into a non-imidazole H₃-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N^α-position followed by removal of the imidazole ring. The resulting compound, N-ethyl-N-(4-phenylbutyl)amine, remarkably has a K_i = 1.3 μM as an H₃ antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N-(5-phenoxypentyl)pyrrolidine (K_i = 0.18 ± 0.10 μM, for [³H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO₂ into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (K_i = 39 ± 11 nM), ED₅₀ = 1.1 ± 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.     

Synthesis and Pharmacology of Combined Histamine H1-/H2-Receptor Antagonists Containing Diphenhydramine and Cyproheptadine Derivatives

The classical histamine H₁-receptor antagonists diphenhydramine ( 3a ) and cyproheptadine ( 9 ) and their derivatives ( 3b—d, 10 ) were connected with a 2-guanidinothiazole containing structure ( 28 ) derived from the H₂-receptor antagonist tiotidine in order to obtain combined H₁-/H₂-receptor antagonists. The two moieties were not directly linked together, but were separated by a polymethylene spacer and a polar group (nitroethenediamine or urea). Thus 12 compounds were obtained that proved in vitro to possess high H₁- and H₂-receptor antagonist activity at the isolated guinea-pig ileum (H₁) and the isolated guinea-pig right atrium (H₂), respectively. The incorporation of the diphenhydramine as well as the cyproheptadine component provides high affinity to H₁-receptors. The tricyclic cyproheptadine and its 10,11-dihydro derivative ( 30–32, 34 ), however, cause a decrease of H₂-receptor antagonist potency compared to the diphenhydramines ( 29a—d, 33a—d ). Using nitroethenediamine as the polar group is apparently more favourable to H₁- and H₂-receptor affinity as the urea function. All compounds elicit a dual mode of competitive and noncompetitive antagonism. Among the novel compounds the nitroethenediamines with 4-fluoro- or 4-methyl-substituted diphenhydramine as H₁-receptor antagonist moiety ( 29c, d ) display the most potent H₁- and H₂-receptor antagonist effects. The presented concept is a very promising way to combine H₁- and H₂-receptor antagonist properties in one molecule.     

Synthesis and Authentication of Iodoazidophenpyramine,a Photoaffinity Reporter Ligand Previously used for Histamine H1-Receptor Labelling

The synthesis is described of aminophenpyramine ( 7 ) (N-{5-[2-(4-aminophenyl)ethananmido]pentanyl}-N′-(4-methoxybenzyl)-N-methyl-N′-(2-pyridinyl)-1,2-ethandiamine), its monoiodo- and diiodo-derivatives ( 8 and 9 ), and iodoazidophenpyramine ( 1 ). The last compound is synthesised by two different routes to confirm the identity of the [¹²⁵I]iodinated ligand previously made only in solution and used for characterisation of the histamine H₁-receptor protein. The procedures employ the novel intermediates 4-amino-3-iodo-phenylacetic acid ( 11 ) and 4-azido-3-iodo-phenylacetic acid ( 13 ). They have general applicability to the synthesis of non-radioactive iodinated photoaffinity receptor ligands which may be required for chemical authentication of the corresponding radiolabelled compounds.     

Histamine H3 receptor ligands break ground in a remarkable plethora of therapeutic areas

The neurotransmitter histamine exerts its action through four distinct histamine receptors. The histamine H₁ and H₂ receptor are well established drug targets, whereas the histamine H₄ receptor is undergoing rigorous characterisation at present. The histamine H₃ receptor (H₃R) is a G_i/o-protein coupled receptor and is mostly expressed in the CNS. A remarkably large and different array of therapeutic areas, in which ligands for the H₃R may prove useful, has been identified and a massive research undertaking is underway to substantiate the high expectations for H₃R ligands. At present, several ligands for the H₃R are being evaluated in clinical studies. In this review, the many potential therapeutic areas for H₃R antagonists, inverse agonists and agonists is discussed. Promising medicinal chemistry and toxicological developments, as well as the advancement of several H₃R ligands into the clinic, will be highlighted. This review also describes the problems that have been overcome and the questions that remain in developing H₃R-related drugs. Considering the tremendous efforts by industry, it can be expected that the first H₃R drugs will reach the market soon.     

Salivary Secretion Evoked by H80/62, (±)-1-(4-hydroxyphenoxy)-3-isopropylamino-2-propranol,a New β1-selective Adrenoceptor Agonist

Abstract H80/62, recently introduced as a β₁-selective adrenoceptor agonist, caused a long-lasting flow of saliva from parotid and submaxillary glands of the rat. The effect of H80/62 was prevented by propranolol or a β₁-selective blocker. The drug did not exert its effect via the sympathetic postganglionic nerves; and it was not taken up by the neuronal amine pump. Sympathetically decentralized or denervated glands acquired a supersensitivity of the postjunctional type to H80/62.     

A New β2-Adrenoceptor Agonist with α1-Adrenoceptor Blocking Properties

Abstract: The phenylethanolamine D2343 exhibits a dualistic adrenoceptormediated effect, i.e. a β-agonistic effect combined with an α-antagonistic one. Tracheal smooth muscles and heart preparations were used to gauge the agonistic effect on adrenergic β-receptors. Rabbit aorta and rat vas deferens were used to determine the α-adrenoceptor blocking activity. The β-adrenoceptor activity of D2343 was classified as β₂-type with about the same efficacy as the β₂-selective terbutaline on tracheal muscle. The effect on isolated heart preparations was greater than that produced by terbutaline. The α-receptor blocking capacity was directed against the α₁-receptor type and was of nearly the same potency as for phentolamine.     

Optimization of a Potent, Orally Active S1P1 Agonist Containing a Quinolinone Core

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1‐[(2,3‐Dihydro‐1‐benzofuran‐2‐yl) methyl]piperazines as novel anti‐inflammatory compounds: Synthesis and evaluation on H3R/H4R

The histamine receptors (HRs) are members of G‐protein‐coupled receptor superfamily and traditional targets of huge therapeutic interests. Recently, H₃R and H₄R have been explored as targets for drug discovery, including in the search for dual‐acting H₃R/H₄R ligands. The H₄R, the most recent histamine receptor, is a promising target for novel anti‐inflammatory agents in several conditions such as asthma and other chronic inflammatory diseases. Due to similarity with previously reported ligands of HRs, a set of 1‐[(2,3‐dihydro‐1‐benzofuran‐2‐yl)methyl]piperazines were synthesized and evaluated in competitive binding assays as H₃R/H₄R ligands herein. The results showed the compounds presented affinity (K_i) for H₃R/H₄R in micromolar range, and they are more selective to H₃R. All the compounds showed no important cytotoxicity to mammalian cells. The phenyl‐substituted compound LINS01005 has shown the higher affinity of the set for H₄R, but no considerable selectivity toward this receptor over H₃R. LINS01005 showed interesting anti‐inflammatory activity in murine asthma model, reducing the eosinophil counts in bronchoalveolar lavage fluid, as well as the COX‐2 expression. The presented compounds are valuable prototypes for further improvements to achieve better anti‐inflammatory agents.     

Analogs of arginine vasopressin modified in position 3 with (R)-α- hydroxymethylphenylalanine

Abstract: This study describes the synthesis and some pharmacological properties of three new analogs of arginine vasopressin (AVP) substituted in position 3 with (R)-α-hydroxymethylphenylalanine ([R]-HmPhe). All new peptides were tested for vasopressor and antidiuretic as well as uterotonic activity. None of the 3 analogs showed any pressor activity and their uterotonic activity was negligible. Only analog [Mpa¹,(R)-HmPhe³]AVP exhibited significant antidiuretic activity.     

Discovery of a Potent,S1P3-Sparing Benzothiazole Agonist of Sphingosine-1-Phosphate Receptor 1 (S1P1)

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Discovery of MK-5046, a Potent,Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

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The selective histamine H1-receptor agonist 2-(3-trifluoromethylphenyl)histamine increases waking in the rat

The effects of the selective histamine H₁-receptor agonist, 2-(3-trifluoromethylphenyl)histamine, were studied in rats implanted with electrodes for chronic sleep recordings. 2-(3-Trifluoromethylphenyl)histamine (80–120 μg) injected into the left lateral ventricle increased wakefulness, whereas slow wave sleep was reduced. Pretreatment with pyrilamine (2.0 mg/kg) prevented the effects of the H₁-receptor agonist on wakefulness and slow wave sleep. Our results further support the involvement of histamine in the modulation of the waking state.     

New 1‐Benzyl‐4‐hydroxypiperidine Derivatives as Non‐imidazole Histamine H3 Receptor Antagonists

A series of 1‐benzyl‐4‐(3‐aminopropyloxy)piperidine and 1‐benzyl‐4‐(5‐aminopentyloxy)piperidine derivatives has been prepared. The 1‐benzyl‐4‐hydroxypiperidine derivatives obtained were evaluated for their affinities at recombinant human histamine H₃ receptor, stably expressed in HEK 293T cells. All compounds investigated show moderate to pronounced in‐vitro affinities. The most potent antagonists in this series 9b2 (hH₃R, pK_i = 7.09), 9b1 (hH₃R, pK_i = 6.78), 9b5 (hH₃R, pK_i = 6.99), and 9b6 (hH₃R, pK_i = 6.97) were also tested in vitro as H₃ receptor antagonists – the electrically evoked contraction of the guinea‐pig jejunum. The histaminergic H₁ antagonism of selected compounds 9b1 , 9b2 , and 9b4 – 9b6 was established on the isolated guinea‐pig ileum by conventional methods; the pA₂ values were compared with the potency of pyrilamine. The compounds did not show any H₁ antagonistic activity (pA₂ < 4; for pyrilamine pA₂ = 9.53).     

Discovery of MK-7725, A Potent,Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Obesity

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Synthesis of N-(4-aminobenzoyl)-γ-oligo (L-glutamic acid)s*

N-(4-aminobenzoyl)-γ-oligo (l -glutamic acid)s (6) containing from two to six glutamic residues have been prepared in solution using Nα-Boc-α-Bzl protections and isobutyl-chlorocarbonate activation. Key steps in the synthesis were the coupling of γ-oligo(α-benzyl l -glutamate) benzyl esters (1) with N-(4-benzyl-oxycarbonylaminobenzoyl)-l -glutamic acid α-benzyl ester (4) to blocked precursors of N-(4-aminobenzoyl)-γ-oligo (l -glutamic acid)s (5) and catalytic hydrogenolysis of 5 to 6. Elaboration of the required oligo γ-l -glutamate chains (1) was achieved step by step beginning with the coupling of glutamic acid dibenzylester with N-(t-butoxycarbonyl)-l -glutamic acid α-benzyl ester (2) to 3 followed by selective removal of the Boc from 3 with HCl-dioxane followed by coupling with 2.     

Brain histamine H receptor occupancy of orally administered antihistamines measured by positron emission tomography with (11)C-doxepin in a placebo-controlled crossover study design in healthy subjects: a comparison of olopatadine and ketotifen

AIMS: The strength of sedation due to antihistamines can be evaluated by using positron emission tomography (PET). The purpose of the present study is to measure histamine H(1) receptor (H(1)R) occupancy due to olopatadine, a new second-generation antihistamine and to compare it with that of ketotifen. METHODS: Eight healthy males (mean age 23.5 years-old) were studied following single oral administration of olopatadine 5 mg or ketotifen 1 mg using PET with (11)C-doxepin in a placebo-controlled crossover study design. Binding potential ratio and H(1)R occupancy were calculated and were compared between olopatadine and ketotifen in the medial prefrontal (MPFC), dorsolateral prefrontal (DLPFC), anterior cingulate (ACC), insular (IC), temporal (TC), parietal (PC), occipital cortices (OC). Plasma drug concentration was measured, and correlation of AUC to H(1)R occupancy was examined. RESULTS: H(1)R occupancy after olopatadine treatment was significantly lower than that after ketotifen treatment in the all cortical regions (P < 0.001). Mean H(1)R occupancies for olopatadine and ketotifen were, respectively: MPFC, 16.7 vs. 77.7; DLPFC, 14.1 vs. 85.9; ACC, 14.7 vs. 76.1; IC, 12.8 vs. 69.7; TC, 12.5 vs. 66.5; PC, 13.9 vs. 65.8; and OC, 19.5 vs. 60.6. Overall cortical mean H(1)R occupancy of olopatadine and ketotifen were 15% and 72%, respectively. H(1)R occupancy of both drugs correlated well with their respective drug plasma concentrations (P < 0.001). CONCLUSION: It is suggested that 5 mg oral olopatadine, with its low H(1)R occupancy and thus minimal sedation, could safely be used an antiallergic treatment for various allergic disorders. Abbreviations histamine H(1) receptor (H(1)R), histamine H(1) receptor occupancy (H(1)RO), dopamine D(2) receptor (D(2)R), positron emission tomography (PET), blood-brain barrier (BBB), binding potential ratio (BPR), distribution volume (DV).     

A three-step synthesis of (±)-β-methyleneaspartic acid

A simplified, three-step synthesis for (±)-β-methyleneaspartic acid is described. Condensation of diethyl malonate with ethyl pyruvate gives 1,1,2–tricarbethoxyprop-1-ene, which is α-aminated with chloramine to give 1-amino-1,1,2-tricarbethoxyprop-2-ene. The latter is hydrolyzed in acid to give the title compound.     

A route to the γ‐secretase inhibitor [2,3,4‐3H]BMS299897 via an α‐phenylselenide derivative

A method for the preparation of [2,3,4‐³H]BMS299897 has been developed. The methyl ester of BMS299897 was oxidized to its double bond derivative, via a phenyl selenide. The resulting double bond was reduced with tritium using Wilkinson's catalyst. The tritiated BMS299897 was isolated, after basic hydrolysis, with a specific activity of 1.6 TBq/mmol. Copyright © 2009 John Wiley & Sons, Ltd.     

Discovery of TUG-770: A Highly Potent Free Fatty Acid Receptor 1 (FFA1/GPR40) Agonist for Treatment of Type 2 Diabetes

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