Rearrangement of Alkylhaloketene-Cyclopentadiene Adducts in Basic Solution--A New Synthesis of 2-Alkyltropones

This research is concerned with determining whether the previously reported synthesis of tropolone by the solvolysis of the dichloroketene-cyclopentadiene adduct in sodium acetate and acetic acid could be used to prepare 2-alkyltropones from the adducts of alkylhaloketenes and cyclopentadiene. The information obtained from these rearrangements could be useful in determining the mechanism of the ring expansion of halogenated ketene-cyclopentadiene adducts to tropone derivatives

Current and prospective pharmacological targets in relation to antimigraine action

Migraine is a recurrent incapacitating neurovascular disorder characterized by unilateral and throbbing headaches associated with photophobia, phonophobia, nausea, and vomiting. Current specific drugs used in the acute treatment of migraine interact with vascular receptors, a fact that has raised concerns about their cardiovascular safety. In the past, α-adrenoceptor agonists (ergotamine, dihydroergotamine, isometheptene) were used. The last two decades have witnessed the advent of 5-HT1B/1D receptor agonists (sumatriptan and second-generation triptans), which have a well-established efficacy in the acute treatment of migraine. Moreover, current prophylactic treatments of migraine include 5-HT2 receptor antagonists, Ca2+ channel blockers, and β-adrenoceptor antagonists. Despite the progress in migraine research and in view of its complex etiology, this disease still remains underdiagnosed, and available therapies are underused. In this review, we have discussed pharmacological targets in migraine, with special emphasis on compounds acting on 5-HT (5-HT1-7), adrenergic (α1, α2, and β), calcitonin gene-related peptide (CGRP 1 and CGRP2), adenosine (A1, A2, and A3), glutamate (NMDA, AMPA, kainate, and metabotropic), dopamine, endothelin, and female hormone (estrogen and progesterone) receptors. In addition, we have considered some other targets, including gamma-aminobutyric acid, angiotensin, bradykinin, histamine, and ionotropic receptors, in relation to antimigraine therapy. Finally, the cardiovascular safety of current and prospective antimigraine therapies is touched upon

4-[2-(3,4-Dimethoxy­phenethyl­amino)prop­oxy]-2-methoxy­benzamide

The title compound, C21H28N2O5, has two intra­molecular N—H⋯O hydrogen bonds. Inter­molecular N—H⋯O hydrogen bonds [graph-set motif R 2 2(8)] give rise to a dimer. Weak N—H⋯N hydrogen bonds between neighboring dimers further extend the crystal structure, which exhibits an infinite chain motif

Effects of Spinal and Peripheral Injection of α1A or α1D Adrenoceptor Antagonists on Bladder Activity in Rat Models with or without Bladder Outlet Obstruction

Purpose Antagonists of α1-adrenergic receptors (α1ARs) relax prostate smooth muscle and relieve voiding and storage symptoms. Recently, increased expression of α1ARs with change of its subtype expression has been proved in bladder outlet obstruction (BOO). To search for the evidence of changes in α1ARs subtype expression and activity in the peripheral and spinal routes, the effects of spinal and peripheral administration of tamsulosin (an α1A/D-selective AR), naftopidil (an α1A/D-selective AR), and doxazosin (non-selective AR) on bladder activity were investigated in a rat model with or without BOO. Methods A total of 65 female Sprague-Dawley rats were divided into the BOO surgery group (n=47) and the sham surgery group (n=18). After 6 weeks, cystometry was assessed before and after intrathecal and intra-arterial administrations of tamsulosin, naftopidil, and doxazosin. Results After intra-arterial administrations of all three drugs, bladder capacity (BC) was increased and maximal intravesical pressure (Pmax) was decreased in both BOO and the sham rat models (P<0.05). After intrathecal administration of all three drugs, BC was increased and Pmax was decreased in only the BOO group. The episodes of involuntary contraction in the BOO rat models were decreased by intra-arterial administration (P=0.031). The increase of BC after intrathercal and intra-arterial administrations of α1ARs was significantly greater in the BOO group than in the sham group (P=0.023, P=0.041). In the BOO group, the increase of BC and decrease in Pmax were greater by intra-arterial administration than by intrathecal administration (P=0.035). There were no significant differences of the degrees of changes in the cystometric parameters among the three different α1ARs. Conclusions Up-regulations of the α1ARs in BOO were observed by the greater increases of BC after α1AR antagonist administrations in the BOO group than in the sham group. However, there were no subtype differences of the α1ARs in functional parameters of bladder activity. In addition, α1ARs also act on the lumbosacral cord which implies that the sensitivity of α1ARs is increased in pathologic models such as BOO. Further evaluation including differential expression of α1ARs in BOO models are need

Expression and function of G-protein-coupled receptorsin the male reproductive tract

This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.Esta revisão enfatiza a expressão e a função dos receptores muscarínicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressão dos receptores muscarínicos e adrenoceptores α1 em compartimentos específicos de dúctulos eferentes, epidídimo, ductos deferentes, vesícula seminal e próstata de várias espécies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do músculo liso, incluindo efeitos na fertilidade masculina. Além disso, a ativação dos receptores muscarínicos leva à transativação do receptor para o fator crescimento epidermal e proliferação das células de Sertoli. Os receptores para relaxina estão presentes no testículo, RXFP1 nas espermátides alongadas e células de Sertoli de rato e RXFP2 nas células de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogênico. A localização de ambos os receptores na porção apical das células epiteliais e no músculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL

Adrenoceptors in GtoPdb v.2023.1

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194]. Adrenoceptors, &#945;1 The three &#945;1-adrenoceptor subtypes &#945;1A, &#945;1B and &#945;1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for &#945;1- relative to &#945;2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of &#945;1-adrenoceptors. &#945;1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being &#945;1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The &#945;1- and &#946;2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of &#945;1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are &#945;1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, &#945;2 The three &#945;2-adrenoceptor subtypes &#945;2A, &#945;2B and &#945;2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for &#945;2- relative to &#945;1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the &#945;2A-adrenoceptor. Multiple mutations of &#945;2-adrenoceptors have been described, some associated with alterations in function. Presynaptic &#945;2-adrenoceptors regulate many functions in the nervous system. The &#945;2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The &#945;2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The &#945;2B subtype appears to be involved in neurotransmission in the spinal cord and &#945;2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, &#946; The three &#946;-adrenoceptor subtypes &#946;1, &#946;2 and &#946;3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for &#946;-adrenoceptors relative to &#945;1- and &#945;2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for &#946;1- and &#946;2- relative to &#946;3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for &#946;1- relative to &#946;2-adrenoceptors. Pharmacological differences exist between human and mouse &#946;3-adrenoceptors, and the \u27rodent selective\u27 agonists BRL 37344 and CL316243 have low efficacy at the human &#946;3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human &#946;3-adrenoceptors [88]. &#946;3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at &#946;3-adrenoceptors, but does not discriminate between the three &#946;- subtypes [332] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label &#946;1- and &#946;2- adrenoceptors and &#946;3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with &#946;1- and &#946;2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track &#946;-adrenoceptors at the cellular level [8]. Somewhat selective &#946;1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. &#946;1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks &#946;1- and &#946;2-adrenoceptors, as well as &#945;1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting &#946;2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation &#946;-adrenoceptor antagonists (propranolol) block both &#946;1- and &#946;2-adrenoceptors and there are no &#946;2-adrenoceptor-selective antagonists used therapeutically. The &#946;3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that &#946;-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197]

Adrenoceptors in GtoPdb v.2023.3

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [64, 194]. Adrenoceptors, &#945;1 The three &#945;1-adrenoceptor subtypes &#945;1A, &#945;1B and &#945;1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for &#945;1- relative to &#945;2-adrenoceptors. [3H]prazosin and [125I]HEAT (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of &#945;1-adrenoceptors. &#945;1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being &#945;1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The &#945;1- and &#946;2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of &#945;1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are &#945;1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, &#945;2The three &#945;2-adrenoceptor subtypes &#945;2A, &#945;2B and &#945;2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine and talipexole are agonists and rauwolscine and yohimbine antagonists selective for &#945;2- relative to &#945;1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the &#945;2A-adrenoceptor. Multiple mutations of &#945;2-adrenoceptors have been described, some associated with alterations in function. Presynaptic &#945;2-adrenoceptors regulate many functions in the nervous system. The &#945;2-adrenoceptor agonists clonidine, guanabenz and brimonidine affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [33] and veterinary medicine and has sympatholytic and anxiolytic properties. The &#945;2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The &#945;2B subtype appears to be involved in neurotransmission in the spinal cord and &#945;2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, &#946; The three &#946;-adrenoceptor subtypes &#946;1, &#946;2 and &#946;3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for &#946;-adrenoceptors relative to &#945;1- and &#945;2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for &#946;1- and &#946;2- relative to &#946;3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for &#946;1- relative to &#946;2-adrenoceptors. Pharmacological differences exist between human and mouse &#946;3-adrenoceptors, and the 'rodent selective' agonists BRL 37344 and CL316243 have low efficacy at the human &#946;3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human &#946;3-adrenoceptors [88]. &#946;3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at &#946;3-adrenoceptors, but does not discriminate between the three &#946;- subtypes [332] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label &#946;1- and &#946;2- adrenoceptors and &#946;3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with &#946;1- and &#946;2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track &#946;-adrenoceptors at the cellular level [8]. Somewhat selective &#946;1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. &#946;1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [528]. Cardiac failure is also treated with carvedilol that blocks &#946;1- and &#946;2-adrenoceptors, as well as &#945;1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting &#946;2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation &#946;-adrenoceptor antagonists (propranolol) block both &#946;1- and &#946;2-adrenoceptors and there are no &#946;2-adrenoceptor-selective antagonists used therapeutically. The &#946;3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that &#946;-adrenoceptor antagonists can reduce metastasis in certain types of cancer [197]

Adrenoceptors in GtoPdb v.2025.3

The nomenclature of the Adrenoceptors has been agreed by the NC-IUPHAR Subcommittee on Adrenoceptors [116, 324]. Adrenoceptors, &#945;1 The three &#945;1-adrenoceptor subtypes &#945;1A, &#945;1B and &#945;1D are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. -(-)phenylephrine, methoxamine and cirazoline are agonists and prazosin and doxazosin antagonists considered selective for &#945;1- relative to &#945;2-adrenoceptors. [3H]prazosin and HEAT (BE2254) (BE2254) are relatively selective radioligands. S(+)-niguldipine also has high affinity for L-type Ca2+ channels. Fluorescent derivatives of prazosin (Bodipy FLprazosin- QAPB) are used to examine cellular localisation of &#945;1-adrenoceptors. &#945;1-Adrenoceptor agonists are used as nasal decongestants; antagonists to treat symptoms of benign prostatic hyperplasia (alfuzosin, doxazosin, terazosin, tamsulosin and silodosin, with the last two compounds being &#945;1A-adrenoceptor selective and claiming to relax bladder neck tone with less hypotension); and to a lesser extent hypertension (doxazosin, terazosin). The &#945;1- and &#946;2-adrenoceptor antagonist carvedilol is used to treat congestive heart failure, although the contribution of &#945;1-adrenoceptor blockade to the therapeutic effect is unclear. Several anti-depressants and anti-psychotic drugs are &#945;1-adrenoceptor antagonists contributing to side effects such as orthostatic hypotension. Adrenoceptors, &#945;2The three &#945;2-adrenoceptor subtypes &#945;2A, &#945;2B and &#945;2C are activated by (-)-adrenaline and with lower potency by (-)-noradrenaline. brimonidine (UK14304) and talipexole are agonists and rauwolscine and yohimbine antagonists selective for &#945;2- relative to &#945;1-adrenoceptors. [3H]rauwolscine, [3H]brimonidine (UK14304) and [3H]RX821002 are relatively selective radioligands. There are species variations in the pharmacology of the &#945;2A-adrenoceptor. Multiple mutations of &#945;2-adrenoceptors have been described, some associated with alterations in function. Presynaptic &#945;2-adrenoceptors regulate many functions in the nervous system. The &#945;2-adrenoceptor agonists clonidine, guanabenz and brimonidine (UK14304) affect central baroreflex control (hypotension and bradycardia), induce hypnotic effects and analgesia, and modulate seizure activity and platelet aggregation. clonidine is an anti-hypertensive (relatively little used) and counteracts opioid withdrawal. dexmedetomidine (also xylazine) is increasingly used as a sedative and analgesic in human [64] and veterinary medicine and has sympatholytic and anxiolytic properties. The &#945;2-adrenoceptor antagonist mirtazapine is used as an anti-depressant. The &#945;2B subtype appears to be involved in neurotransmission in the spinal cord and &#945;2C in regulating catecholamine release from adrenal chromaffin cells. Although subtype-selective antagonists have been developed, none are used clinically and they remain experimental tools. Adrenoceptors, &#946; The three &#946;-adrenoceptor subtypes &#946;1, &#946;2 and &#946;3 are activated by the endogenous agonists (-)-adrenaline and (-)-noradrenaline. Isoprenaline is selective for &#946;-adrenoceptors relative to &#945;1- and &#945;2-adrenoceptors, while propranolol (pKi 8.2-9.2) and cyanopindolol (pKi 10.0-11.0) are relatively selective antagonists for &#946;1- and &#946;2- relative to &#946;3-adrenoceptors. (-)-noradrenaline, xamoterol and (-)-Ro 363 show selectivity for &#946;1- relative to &#946;2-adrenoceptors. Pharmacological differences exist between human and mouse &#946;3-adrenoceptors, and the \u27rodent selective\u27 agonists BRL 37344 and CL316243 have low efficacy at the human &#946;3-adrenoceptor whereas CGP 12177 (low potency) and L 755507 activate human &#946;3-adrenoceptors [88]. &#946;3-Adrenoceptors are resistant to blockade by propranolol, but can be blocked by high concentrations of bupranolol. SR59230A has reasonably high affinity at &#946;3-adrenoceptors, but does not discriminate between the three &#946;- subtypes [520] whereas L-748337 is more selective. [125I]-cyanopindolol, [125I]-hydroxy benzylpindolol and [3H]-alprenolol are high affinity radioligands that label &#946;1- and &#946;2- adrenoceptors and &#946;3-adrenoceptors can be labelled with higher concentrations (nM) of [125I]-cyanopindolol together with &#946;1- and &#946;2-adrenoceptor antagonists. Fluorescent ligands such as BODIPY-TMR-CGP12177 can be used to track &#946;-adrenoceptors at the cellular level [8]. Somewhat selective &#946;1-adrenoceptor agonists (denopamine, dobutamine) are used short term to treat cardiogenic shock but, chronically, reduce survival. &#946;1-Adrenoceptor-preferring antagonists are used to treat cardiac arrhythmias (atenolol, bisoprolol, esmolol) and cardiac failure (metoprolol, nebivolol) but also in combination with other treatments to treat hypertension (atenolol, betaxolol, bisoprolol, metoprolol and nebivolol) [820]. Cardiac failure is also treated with carvedilol that blocks &#946;1- and &#946;2-adrenoceptors, as well as &#945;1-adrenoceptors. Short (salbutamol, terbutaline) and long (formoterol, salmeterol) acting &#946;2-adrenoceptor-selective agonists are powerful bronchodilators used to treat respiratory disorders. Many first generation &#946;-adrenoceptor antagonists (propranolol) block both &#946;1- and &#946;2-adrenoceptors and there are no &#946;2-adrenoceptor-selective antagonists used therapeutically. The &#946;3-adrenoceptor agonist mirabegron is used to control overactive bladder syndrome. There is evidence to suggest that &#946;-adrenoceptor antagonists can reduce metastasis in certain types of cancer [327]