[]RS79948-197 binding to human, rat, guinea pig and pig α2A-, α2B- and α2C-adrenoceptors. Comparison with MK912, RX821002, rauwolscine and yohimbine

Uhlén, Staffan; Dambrova, Maija; Näsman, Johnny; Schiöth, Helgi B.; Gu, Yuchen; Wikberg-Matsson, Anna; Wikberg, Jarl E. S.

doi:10.1016/s0014-2999(97)01521-5

Cited by 84 publications

(42 citation statements)

References 26 publications

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“…17 The selective a 2 -adrenoceptor antagonist, RS79948, has high affinity for each of the a 2A -, a 2B -and a 2C -adrenoceptors, whereas RX821002, another widely used a 2 -adrenoceptor antagonist, exhibits higher affinity for a 2A -than the a 2B -and a 2C -subtypes. 30,31 In the present study, RS79948 alone increased colonic temperature above that of control animals during the second half of the experiment. However, RS79948 neither antagonized nor potentiated the effect of M2 on colonic temperature, indicating that these a 2 -adrenoceptor subtypes are not involved in M2-induced thermogenesis.…”

Section: Discussionsupporting

confidence: 53%

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

Heal

2002

Int J Obes

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OBJECTIVE:To investigate the pharmacological mechanisms underlying the induction of thermogenesis by Metabolite 2 (M2; BTS 54 505), a major pharmacologically active metabolite of the anti-obesity drug, sibutramine. DESIGN: Adult female Wistar rats were treated with M2 or vehicle, with or without various monoamine receptor antagonists, prazosin, RS79948, metergoline, propranolol and ( þ )butaclamol. MEASUREMENTS: Colonic temperature and food intake at room temperature (21 AE 1 C), thermoregulatory behavioural response, operant responding for exogenous heat at 7 8 C and oxygen consumption at thermoneutrality (29 C). RESULTS: M2 (10 mg=kg, p.o.) significantly increased colonic temperature during the 4.5 h period following drug administration. This effect was abolished by the non-selective 5-HT receptor antagonist, metergoline (1 mg=kg, p.o.), and a 1 -adrenoceptor antagonist, prazosin (1 mg=kg, p.o.), measured at 1.5 -2.5 h post-M2 administration, and was partially antagonized by each antagonist at 3.5 -4.5 h. The non-selective b-adrenoceptor antagonist, propranolol (1 mg=kg, p.o.), had no effect on the M2-induced increase in colonic temperature, whereas at 20 mg=kg (p.o.), propranolol partially inhibited the effect of M2 on colonic temperature. By contrast, the selective a 2 -adrenoceptor antagonist, RS79948 (1 mg=kg, p.o.), and the D2=D1 receptor antagonist, ( þ )butaclamol (200 mg=kg, p.o.), did not alter the effect of M2 on colonic temperature. In the thermoregulatory study, M2 (10 mg=kg, i.p.)-treated rats required significantly less radiant heat at 7 8 C to maintain body temperature, and this effect was not affected by the D2=D1 receptor antagonist ( þ )butaclamol (100 mg=kg 71 , i.p.). The hypophagia induced by M2 (10 mg=kg) measured up to 24 h was partially antagonized by the a 1 -adrenoceptor antagonist, prazosin, whereas metergoline, RS79948, propranolol and ( þ )butaclamol had no effect on M2-induced hypophagia. CONCLUSION: It is concluded that 5-HT, a 1 -and b 3 -adrenoceptors are involved in the induction of thermogenesis by M2, whereas the hypophagic effect is mainly mediated via a 1 -adrenoceptors. These findings are consistent with M2 increasing 5-HT and noradrenaline tone via potent reuptake inhibition which subsequently results in increased efferent sympathetic activity to brown adipose tissue (BAT).

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Section: Discussionsupporting

confidence: 53%

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

Heal

2002

Int J Obes

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“…The isoproterenol-stimulated internalization of ␣ 2C AR observed here suggests a mechanism that may underlie various forms of cross-talk that have been reported between ␤ 2 ARs and ␣ 2 ARs (Maggi et al, 1980;Northam and Mobley, 1985;Nakamura et al, 1991;Atkinson and Minneman, 1992;Birnbaum et al, 1995). It is known that ␣ 2C AR and ␤ 2 AR are coexpressed in many of the same tissues, including distinct structures within the brain, adrenal glands, and kidney (Rainbow et al, 1984;Rosin et al, 1996;Lee et al, 1998;Uhlen et al, 1998;Brede et al, 2003;Cesetti et al, 2003;Wallace et al, 2004). Further investigations into the consequences of ␣ 2C AR/␤ 2 AR associations in native tissues, e.g., studies on knockout mice, may shed additional light on the physiological importance of the interaction between these receptors in vivo.…”

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confidence: 52%

α_2C-Adrenergic Receptors Exhibit Enhanced Surface Expression and Signaling upon Association with β₂-Adrenergic Receptors

Prinster

Holmqvist²,

Hall³

2006

J Pharmacol Exp Ther

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The ␣ 2C -adrenergic receptor (␣ 2C AR) is known to be poorly trafficked to the cell surface when expressed in a variety of cell types. We tested the hypothesis that the surface expression and signaling of ␣ 2C AR might be enhanced by heterodimerization with other G protein-coupled receptors (GPCRs). Cotransfection of ␣ 2C AR with more than 25 related GPCRs revealed that only coexpression with the ␤ 2 -adrenergic receptor (␤ 2 AR) increased the surface localization of ␣ 2C AR in human embryonic kidney-293 cells. Coimmunoprecipitation of ␣ 2C AR with ␤ 2 AR confirmed a physical interaction between the two receptors. Confocal microscopy studies demonstrated that ␣ 2C AR expressed alone was mainly intracellular, whereas ␣ 2C AR coexpressed with ␤ 2 AR was predominantly localized to the plasma membrane. Ligand binding studies revealed a significant increase in ␣ 2C AR binding sites upon coexpression with ␤ 2 AR, with no apparent change in affinity for ␣ 2 AR ligands. Functional assays with the ␣ 2 AR-specific agonist brimonidine (UK 14,304) revealed that coexpression of ␤ 2 AR with ␣ 2C AR enhanced ␣ 2C AR-mediated activation of extracellular signalregulated kinase 1/2. Furthermore, analyses of agonist-promoted receptor endocytosis demonstrated enhanced ␣ 2C AR internalization in response to ␣ 2 AR agonists when ␣ 2C AR and ␤ 2 AR were coexpressed. In addition, substantial cointernalization of ␣ 2C AR in response to ␤AR agonists was observed when ␣ 2C AR was coexpressed with ␤ 2 AR. These data reveal that ␣ 2C AR can interact with ␤ 2 AR in cells in a manner that regulates ␣ 2C AR surface expression, internalization, and functionality.The adrenergic receptors are a family of cell-surface G protein-coupled receptors (GPCRs) that mediate the actions of the hormone epinephrine and the neurotransmitter norepinephrine. The three main adrenergic receptor (AR) classes (␣ 1 , ␣ 2 , and ␤ 2 ) can be further divided into three subtypes each, and all of these subtypes are excellent targets for therapeutic pharmaceuticals. The specific roles of the various adrenergic receptor subtypes is becoming increasingly clear through studies on knock-out mice (Philipp and Hein, 2004), and novel therapies making use of these insights await the development of more subtype-specific drugs. However, two of the adrenergic receptor subtypes, ␣ 2C AR and ␣ 1D

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“…It is an alkaloid derived from the bark of the Central African tree Corynanthe johimbe and shows relatively high af®nity (3±4 nM) for human a 2A and a 2C receptors, and moderate af®nity (14 nM) for the a 2B receptor subtype (67). It has been known for many years that this drug facilitates sexual activity in several experimental models, acting on a 2 adrenoceptors present in the central nervous system (68,69).…”

Section: Clinical Results With a Adrenoceptor Antagonists In Edmentioning

confidence: 99%

Erectile dysfunction: from biochemical pharmacology to advances in medical therapy

et al. 2000

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Research on penile smooth muscle physiology has increased the number of drugs available for treating erectile dysfunction (ED). Penile erection involves the relaxation of smooth muscle in the corpus cavernosum. The key mediator of smooth muscle relaxation is nitric oxide (NO), which acts by increasing the cellular level of cGMP. Another cyclic nucleotide, cAMP, is involved in smooth muscle cell relaxation; cAMP formation is stimulated by a number of compounds, such as alprostadil. An increase in cAMP and/or cGMP levels can also be induced by inhibition of phosphodiesterases (PDEs), the enzymes involved in cyclic nucleotide breakdown. Both papaverine and sildena®l are PDE inhibitors. Papaverine is a non-speci®c inhibitor of these enzymes; sildena®l is an orally active, potent and selective inhibitor of GMP-speci®c PDE5, the predominant isoenzyme metabolizing cGMP in the cells of the corpus cavernosum. Penile smooth muscle contraction, induced by adrenergic ®bers through a 1 adrenoceptors, produces detumescence, thus making a adrenoceptor antagonists suitable for maintenance of penile erection. The orally active drug yohimbine is a mixed a 1 -a 2 adrenoceptor antagonist that works by a dual mechanism; it facilitates sexual arousal by acting on a 2 adrenoceptors in the central nervous system and blocks adrenergic in¯uences at peripheral level.

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[]RS79948-197 binding to human, rat, guinea pig and pig α2A-, α2B- and α2C-adrenoceptors. Comparison with MK912, RX821002, rauwolscine and yohimbine

Cited by 84 publications

References 26 publications

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

α_2C-Adrenergic Receptors Exhibit Enhanced Surface Expression and Signaling upon Association with β₂-Adrenergic Receptors

Erectile dysfunction: from biochemical pharmacology to advances in medical therapy

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[]RS79948-197 binding to human, rat, guinea pig and pig α2A-, α2B- and α2C-adrenoceptors. Comparison with MK912, RX821002, rauwolscine and yohimbine

Cited by 84 publications

References 26 publications

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

Mechanism of the thermogenic effect of Metabolite 2 (BTS 54 505), a major pharmacologically active metabolite of the novel anti-obesity drug, sibutramine

α2C-Adrenergic Receptors Exhibit Enhanced Surface Expression and Signaling upon Association with β2-Adrenergic Receptors

Erectile dysfunction: from biochemical pharmacology to advances in medical therapy

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Product

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α_2C-Adrenergic Receptors Exhibit Enhanced Surface Expression and Signaling upon Association with β₂-Adrenergic Receptors