Cellular coupling of beta₃-adrenoceptors (β₃-ADR) to potassium channels in myometrium is largely unknown. In vitro study was undertaken to unravel the presence of β₃-adrenergic receptors (ADR) and the role of K⁺-channels in mediating β₃-ADR-induced relaxation in isolated myometrial strips from cyclic non-pregnant water buffaloes. Isometric tension was recorded in isolated myometrial strips using data acquisition system based physiograph. Compared to SR 59230A, BRL 37344 was found to be more potent in inducing β₃-dependent myometrial relaxation which was significantly (p < 0.05) inhibited in the presence of β₃ antagonist, SAR 150640. The immunoreactive protein to β₃-ADR was also detected in membrane fraction of myometrial protein. Further, incubation with BRL 37344 (10 μM) significantly (p < 0.05) increased c-AMP accumulation (37.58 ± 9.52 pmol/mg protein; n = 4) in the myometrial strips compared to basal c-AMP level (16.85 ± 3.87 pmol/mg protein; n = 4). The concentration response curves (CRC) of BRL 37344 were significantly (p < 0.05) shifted towards right in the presence of K_ATP channels specific blocker, glibenclamide (10 μM) and maxi K⁺-channels (BK_Ca) specific blocker, iberiotoxin (100 nM), with decrease in both efficacy and potency as compared to control. However, 4-aminopyridine (4-AP), a specific blocker of the voltage gated K⁺-channels (Kv), failed to alter the CRC of BRL 37344. Existence of immunoreactive protein to Kir6.1, α-subunit of BK_Ca and Kv1.1 channels were also detected in the membrane fraction of myometrial protein. Based on the above findings, it can be concluded that BRL 37344 is a potent stimulator of β₃-adrenoceptors in buffalo myometrium and besides mediating their effect through rise in c-AMP, they are coupled to K_ATP and BK_Ca channels in inducing tocolytic effects.

01 May 2013·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

Biphasic Erk1/2 activation sequentially involving Gs and Gi signaling is required in beta3-adrenergic receptor-induced primary smooth muscle cell proliferation

Article

Author: Tarik Hadi ; Marc Bardou ; Pascal Mourtialon ; Carmen Garrido ; Paul Sagot ; Maeva Wendremaire ; Frédéric Lirussi ; Marina Barrichon

The beta3 adrenergic receptor (B3-AR) reportedly induces cell proliferation, but the signaling pathways that were proposed, involving either Gs or Gi coupling, remain controversial. To further investigate the role of G protein coupling in B3-AR induced proliferation, we stimulated primary human myometrial smooth muscle cells with SAR150640 (B3-AR agonist) in the absence or presence of variable G-protein inhibitors. Specific B3-AR stimulation led to an Erk1/2 induced proliferation. We observed that the proliferative effects of B3-AR require two Erk1/2 activation peaks (the first after 3min, the second at 8h). Erk1/2 activation at 3min was mimicked by forskolin (adenylyl-cyclase activator), and was resistant to pertussis toxin (Gi inhibitor), suggesting a Gs protein signaling. This first signaling also required the downstream Gs signaling effectors PKA and Src. However, Erk1/2 activation at 8h turned out to be pertussis toxin-dependent, and PKA-independent, indicating a Gi signaling pathway in which Src and PI3K were required. The pharmacological inhibition of both the Gs and Gi pathway abolished B3-AR-induced proliferation. Altogether, these data indicate that B3-AR-induced proliferation depends on the biphasic activation of Erk1/2 sequentially induced by the Gs/PKA/Src and Gi/Src/PI3K signaling pathways.

01 Jan 2013·European Journal of PharmacologyQ3 · MEDICINE

Molecular and functional characteristics of β3-adrenoceptors in late pregnant mouse uterus: A comparison with β2-adrenoceptors

Q3 · MEDICINE

Article

Author: Mishra, Santosh K. ; Parida, Subhashree ; Ravi Prakash, Vellanki ; Uttam Singh, Thakur

β(3)-adrenoceptor is a potential target for uterine relaxant drugs for the treatment of preterm labor. Mouse is an ideal experimental model for preterm labor. However, there is limited information on the molecular and functional characteristics of β(3)-adrenoceptors in mouse uterus. Therefore, the current study was undertaken to characterize the β(3)-adrenoceptors in late pregnant mouse uterus by molecular and functional experiments and to compare their expression and function with the β(2)-adrenoceptors. Using RT-PCR, we demonstrated the presence of β(3)-adrenoceptor mRNA in the mouse uterus. Accordingly, selective β(3)-adrenoceptor agonist SAR150640 (ethyl-4-{trans-4-[((2S)-2-hydroxy-3-{4-hydroxy-3[(methylsulfonyl)amino]-phenoxy}propyl)amino]cyclohexyl}benzoate hydrochloride) caused concentration-dependent relaxation of the isolated tissue. SR59230A (1 μM), a selective antagonist of β(3)-adrenoceptors, antagonized the relaxant response to SAR150640. Using real-time PCR we found that in comparison to β(3)-adrenoceptor mRNA, β(2)-adrenoceptor mRNA is predominantly expressed in the late pregnant mouse uterus. We then assessed the comparative efficiency of different β-adrenoceptor agonists, such as SAR150640, salbutamol and isoprenaline to relax the tissue. SAR150640 (pD(2) 6.64±0.21, E(max) 104.9±7.95), salbutamol (pD(2) 8.57±0.062, E(max) 103.1±3.22) and isoprenaline (pD(2) 9.48±0.084, E(max) 102.9±5.18) caused concentration-dependent inhibition of uterine rhythmic contractions. While the maximal relaxation to these agonists was comparable, the order of potency was isoprenaline>salbutamol>SAR. These results suggest that β(3)-adrenoceptor mRNA is present in the pregnant mouse uterus and is functionally active. The predominance of β(2)- over β(3)-adrenoceptor expression may explain variable potency amongst the β-adrenoceptor agonists.

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Indication	Highest Phase	Country/Location	Organization	Date
Obstetric Labor, Premature	Discovery	FR	Sanofi SA	-

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