Novel selective β ₁ ‐adrenoceptor antagonists for concomitant cardiovascular and respiratory disease

Figures

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  Figure 1.. Chemical structures of β1-selective β-blockers.

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  Figure 2.. Inhibition of 3H-CGP12177 whole-cell binding in response to CGP20712A, ICI118551, NDD-713, and NDD-825 in CHO-β1 (A) and CHO-β2 (B) cells. Nonspecific binding was determined by 10 μM propranolol. Data points are means ± sem of triplicate determinations, and the concentrations of 3H-CGP12177 present in these experiments was 0.89 nM. These single experiments are representative of 20 (A) and 16 (B) separate experiments.

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  Figure 3.. 3H-cAMP accumulation in response to cimaterol in the absence or presence of bisoprolol (A), NDD-713 (B), and NDD-825 (C) in CHO-β1 and CHO-β2 cells. Bars represent basal 3H-cAMP accumulation and accumulation in response to 10 μM isoprenaline or β-blocker alone. Data points are means ± sem of triplicate determinations, and these single experiments are representative of 5 (A), 4 (B), and 3 (C) separate experiments in each case.

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  Figure 4.. Inhibition of specific 3H-CGP12177 whole-cell binding in CHO-β1 cells in response to bisoprolol (A), NDD-713 (B), and -825 (C), with the control curve (solid circles) and after washout of the competing β-blocker (open circles) as described in Materials and Methods. Nonspecific binding was determined by 10 μM propranolol. Data points are means ± sem of triplicate determinations, and the concentrations of 3H-CGP12177 present in these experiments were 0.81 nM (A), 0.96 nM (B), and 0.74 nM (C). These single experiments are representative of 4 (A), 9 (B), and 8 (C) separate experiments.

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  Figure 5.. A) 3H-cAMP accumulation in CHO-β1 cells in response to NDD-713 and -825. Bars represent basal 3H-cAMP accumulation, in response to 10 μM isoprenaline alone, and in response to 10 μM carvedilol alone. Data points are means ± sem of triplicate determinations, and these single experiments are representative of 8 separate experiments in each case. B) CRE-SPAP production in CHO-β1 cells in response to NDD-713 and -825. Bars represent basal CRE-SPAP production, in response to 10 μM isoprenaline alone, and in response to 10 μM carvedilol alone. Data points are means ± sem of triplicate determinations and are representative of 5 separate experiments in each case. C) Basal and ERK1/2 MAPK activation in CHO-β1 cells in response to phorbol ester, carvedilol, NDD-713, and -825 (5 min incubation). Bars are means ± sem of triplicate determinations. This single experiment is representative of 4 separate experiments.

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  Figure 6.. Receptor selectivity of CGP20712A (at 10 μM; A), LK204-545 (at 10 μM; B), NDD-713 (at 4.8 μM; C), and -825 (at 2.4 μM; D). The compounds were assayed against the receptors listed in duplicate and average values are shown. Values for β-ARs are shown as black circles, those for receptors with >50% inhibition as red circles, those in the range of 30–50% inhibition as orange circles, and those with <30% inhibition as open circles. GPCRs: adenosine (A1, A2, A3), adrenoceptor (α1, α2, β1, β2), angiotensin (AT1, AT2), benzodiazepine, central and peripheral (cBZD, pBZD), bombesin (BB), bradykinin (B2), chemokine (CGPR, CXCR2, CCR1), cannabinoid (CB1), cholecystokinin (CCK1, CCK2), cytokine (TNF-α), dopamine (D1, D1S, D3, D4.4, D5), endothelin (ETA, ETB), GABA, galanin (GAL1, GAL2), histamine (H1, H2), melanocortin (MC4), motilin (MT1), muscarinic acetylcholine (M1, M2, M3, M4, M5), neurokinin (NK1, NK2, NK3), neuropeptide Y (Y1, Y2), neurotensin (NTS1), nociception (NOP), opioid (DOP, KOP, MOP), prostaglandin (EP2, EP4, IP), pituitary adenylate cyclase-activating polypeptide (PAC1), purinergic (P2X, P2Y), serotonergic (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2B, 5-HT2C, 5-HT3, 5-HT5A, 5-HT-6,…

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  Figure 7.. PK profiles of bisoprolol (A), NDD-713.HCl (B), and -825.HCl (C) after single bolus intravenous or oral. administration of compounds to rats. Plasma drug levels were corrected for plasma protein binding (see Table 5). Plasma fu levels of compounds are plotted as a function of time postadministration (values are means ± sd; n = 3). Concentrations corresponding to human and rat β-AR Kd values of the 3 compounds are shown as colored lines. Thus, to be effective, drug levels need to be above the blue lines to achieve β1-blockade, but below the red lines to avoid β2-blockade.

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  Figure 8.. Selectivity of various β-blockers in vivo. Responses to isoprenaline before and after administration of intravenous saline or β-blockers in conscious, atropine-treated, freely moving rats. Absolute values for HR and HQC were measured before (first value of each linked series) and at the end of 3-min infusions of isoprenaline (12, 40, and 120 ng/kg/min; remaining 3 values in each linked series). Isoprenaline was administered before (control, solid circles), during (open circles), 3–4 h after (solid triangles), and 23–24 h after (open triangles) the intravenous infusion of saline (0.1 ml/kg bolus; 0.4 ml/kg/h infusion; A), CGP20712A (200 μg/kg bolus; 100 μg/kg/h infusion; B), ICI118551 (2 mg/kg bolus; 1 mg/kg/h infusion; C), and bisoprolol (2 mg/kg bolus; 1 mg/kg/h infusion; D), NDD-713.HCl (2 mg/kg bolus: 1 mg/kg/h infusion; E), and NDD-825.HCl (2 mg/kg bolus; 1 mg/kg/h infusion; F). Values are means ± sem (n = 4). *P < 0.05 vs. baseline before β-blocker; #P < 0.05 vs. isoprenaline maximum value before β-blocker (Quade test).

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  Figure 9.. Responses to isoprenaline before and after administration of β-blockers in conscious, atropine-treated, freely moving rats. Absolute values for HR and HQC were measured before (first value of each linked series) and at the end of 3-min infusions of isoprenaline (12, 40, and 120 ng/kg/min; remaining 3 values in each linked series). Isoprenaline was administered before (control, solid circles), 1 h (open circles), and 3 h (open triangles) after NDD-825.HCl, p.o. at a dose of 1 mg/kg (d 1), 3 mg/kg (d 2), and 10 mg/kg (d 3). Values are means ± sem (n = 3 rats). *P < 0.05 vs. baseline before β-blocker; #P < 0.05 vs. isoprenaline maximum value before β-blocker (Quade test).