ZD 2079

Ligands at beta2-, beta3-, and the low-affinity state of beta1-adrenoceptors block the alpha1-adrenoceptor-mediated constriction in human pulmonary and rat mesenteric arteries.[Pubmed:15965358]

J Cardiovasc Pharmacol. 2005 Jul;46(1):76-82.

We examined whether the beta2-adrenoceptor agonists fenoterol and salbutamol, the beta3-adrenoceptor agonists CL 316243 and ZD 2079, and the agonists of the low-affinity state of beta-adrenoceptors, cyanopindolol and CGP 12177 block alpha1-adrenoceptors in that concentration range in which they relax the human pulmonary and rat mesenteric arteries preconstricted with phenylephrine 10 microM and 1 microM, respectively. For quantification of vasodilatation pEC25 values and for the antagonism toward alpha1-adrenoceptors, pA2 values were determined. We found that in the rat mesenteric artery, (1) the pEC25 values of the beta-adrenoceptor ligands resemble their respective pA2 values (difference < or = 0.9 log units), and (2) the order of potencies is the same for both parameters, ie, cyanopindolol approximately fenoterol > CGP 12177 > salbutamol > ZD 2079 > CL 316243. In the human pulmonary artery, (1) the pEC25 values are slightly lower (by 0.6-1.3 log units) than their respective pA2 values, and (2) the rank order of potencies is the same for both parameters. In conclusion, the present study suggests that ligands of beta2-adrenoceptors and of non-beta1-non-beta2-adrenoceptors relax rat and human vessels preconstricted with phenylephrine or norepinephrine mainly through their alpha1-adrenolytic effects. Hence, for the investigation of the role of beta-adrenoceptors in vessels, the constrictor agent should be chosen with great caution.

A search for presynaptic beta3-adrenoceptors in the rat.[Pubmed:15810894]

Fundam Clin Pharmacol. 2005 Apr;19(2):147-53.

Presynaptically localized adrenoceptors occur on a variety of neurones. In particular, alpha2-adrenoceptors, occurring on neurones of the peripheral and central nervous system, inhibit the release of the respective transmitters whereas beta2-adrenoceptors on some types of postganglionic sympathetic neurones facilitate noradrenaline release. Since only little information is available whether there are also presynaptic beta3-adrenoceptors, we examined the effect of beta3-adrenoceptor agonists on noradrenaline release from the resistance vessels and the hippocampus of the rat and on serotonin and acetylcholine release from the rat hippocampus. In rat hippocampal slices preincubated with (H-noradrenaline, 3H-serotonin and 3H-choline and superfused in the presence of an inhibitor of the neuronal transporter of the respective neurone, the beta3-adrenoceptor agonist CL 316243 did not affect the electrically evoked tritium overflow. The latter was, however, inhibited by at least 50% by agonists of the respective autoreceptors. CL 316243 and another three beta3-adrenoceptor agonists (BRL 37344, ZD 2079 and CGP 12177) failed to affect the electrically evoked tritium overflow also in slices preincubated with 3H-noradrenaline and superfused in the presence of the alpha2-adrenoceptor antagonist rauwolscine whereas prostaglandin E2 caused a marked inhibition. In pithed and vagotomized rats, the increase in diastolic blood pressure induced by electrical stimulation of the sympathetic outflow was also not affected by CL 316243 but markedly inhibited by the cannabinoid receptor agonist WIN 55212-2. CL 316243 and WIN 55212-2 were devoid of an effect on the rise in diastolic blood pressure induced by exogenous noradrenaline. In conclusion, our data suggest that the noradrenergic neurones innervating the resistance vessels of the rat and the noradrenergic, serotoninergic and cholinergic neurones of the rat hippocampus are not endowed with presynaptic beta3-adrenoceptors.

Atypical beta-adrenoceptors, different from beta 3-adrenoceptors and probably from the low-affinity state of beta 1-adrenoceptors, relax the rat isolated mesenteric artery.[Pubmed:12967929]

Br J Pharmacol. 2003 Sep;140(1):3-12.

(1) We examined whether beta3- and/or atypical beta-adrenoceptors relax the rat isolated mesenteric artery. (2) Mesenteric arteries precontracted with phenylephrine were relaxed by beta-agonists with the following potencies (pD2): nonselective agonist isoprenaline (6.00)>nonconventional partial agonist cyanopindolol (5.45)>beta2-agonist fenoterol (4.98)>nonconventional partial agonist CGP 12177 (4.19)>beta3-agonist ZD 2079 (3.72). The beta3-agonist CL 316243 1 mm relaxed the vessel only marginally. (3) The concentration-response curves (CRCs) for cyanopindolol, CGP 12177 and ZD 2079 were not affected by the nonselective beta-antagonist propranolol 0.3 microm, the beta2-antagonist ICI 118551 1 microm and by CL 316243 60 microm, but shifted to the right by bupranolol (pA2 5.3-5.7), CGP 20712 (5.4) and SR 59230A (6.5-6.7) (the latter three drugs block atypical and/or beta3-adrenoceptors at high concentrations). (4) The CRC for isoprenaline was shifted to the right by propranolol (pA2 7.0) but, in the presence of propranolol 0.3 microm, not affected by SR 59230A 1 microm. The CRC for fenoterol was shifted to the right by propranolol (pA2 6.9) and ICI 118551 (6.8). (5) Removal of endothelium diminished the vasorelaxant effects of cyanopindolol, CGP 12177 and ZD 2079. (6) Fenoterol and cyanopindolol also relaxed (endothelium-intact) mesenteric arteries precontracted with serotonin. The relaxant effect of cyanopindolol was antagonized by bupranolol to about the same degree as in phenylephrine-contracted vessels. (7) In conclusion, beta2- and atypical beta-adrenoceptors (but not beta3-adrenoceptors) relax the rat mesenteric artery. The atypical beta-adrenoceptor, which is partially located endothelially, may differ from the low-affinity state of the beta1-adrenoceptor.

Evaluation of beta3-adrenoceptor-mediated relaxation in intact and endotoxin-treated equine digital veins.[Pubmed:12828256]

Am J Vet Res. 2003 Jun;64(6):708-14.

OBJECTIVE: To investigate the functional expression of beta3-adrenoceptors (beta3-ARs) in equine digital veins (EDVs) and to examine whether beta3-AR relaxation was altered in EDVs incubated with endotoxin. SAMPLE POPULATION: Forelimbs obtained from 30 horses. PROCEDURE: Forelimbs were obtained from horses in an abattoir. Equine digital veins were carefully removed from distal portions of the forelimbs. Rings of dissected EDVs were mounted in 5-mL organ baths to record isometric tension in the presence of various beta3-AR agonists (SR 58611A, ZD 2079, and ZM 215001). RESULTS: In intact EDVs, isoprenaline, SR 58611A, ZD 2079, and ZM 215001 induced concentration-dependent relaxation. Isoprenaline and SR 58611A-induced relaxations were reduced or unaffected by nadolol, respectively. In intact EDVs, SR 58611A-induced relaxation was significantly reduced in the presence of 2 microM ZM 215001 (used as a beta3-AR antagonist). In endothelium-denuded EDVs or intact EDVs in the presence of a nitric oxide synthase inhibitor, isoprenaline and SR 58611A-induced relaxations were significantly decreased. The endothelium-independent relaxation to SR 58611A was significantly inhibited in the presence of ZM 215001. In endotoxin-treated EDV, isoprenaline- and SR 58611A-induced relaxations were significantly reduced. In these conditions, cycloheximide (a protein synthesis inhibitor) and ibuprofen (a cyclooxygenase inhibitor) restored the relaxant response to SR 58611A. CONCLUSIONS AND CLINICAL RELEVANCE: Beta3-adrenoceptors are functionally expressed in EDVs. Incubation in the presence of endotoxin, used as an in vitro model of laminitis, induced an alteration of beta-AR-mediated relaxations in EDVs, which could be the consequence of cyclooxygenase induction and subsequent prostanoid production.

Beta 1-, beta 2- and atypical beta-adrenoceptor-mediated relaxation in rat isolated aorta.[Pubmed:10683187]

Br J Pharmacol. 2000 Feb;129(4):637-44.

beta-adrenoceptor-mediated relaxation was investigated in ring preparations of rat isolated thoracic aorta. Rings were pre-constricted with a sub-maximal concentration of noradrenaline (1 microM) and relaxant responses to cumulative concentrations of beta-adrenoceptor agonists obtained. The concentration-response curve (CRC) to isoprenaline was shifted to the right by propranolol (0.3 microM) with a steepening of the slope. Estimation of the magnitude of the shift from EC(50) values gave a pA(2) of 7.6. Selective beta(1)- and beta(2)-adrenoceptor antagonists, CGP 20712A (0.1 microM) and ICI 118551 (0.1 microM), respectively, produced 4 and 14 fold shifts of the isoprenaline CRC. Atypical beta-adrenoceptor agonists also produced concentration-dependent relaxation of aortic rings. The order of potency of the beta-adrenoceptor agonists was (-log EC(50)): isoprenaline (6. 25)>cyanopindolol (5.59)>isoprenaline+propranolol (5.11)>CGP 12177A (4.40)>ZD 2079 (4.24)>ZM 215001 (4.07)>BRL 37344 (3.89). Relaxation to CGP 12177A and ZM 215001 was unaffected by propranolol (0.3 microM). SR 59230A (

Validity of (-)-[3H]-CGP 12177A as a radioligand for the 'putative beta4-adrenoceptor' in rat atrium.[Pubmed:9504376]

Br J Pharmacol. 1998 Feb;123(3):371-80.

1. We have recently suggested the existence in the heart of a 'putative beta4-adrenoceptor' based on the cardiostimulant effects of non-conventional partial agonists, compounds that cause cardiostimulant effects at greater concentrations than those required to block beta1- and beta2-adrenoceptors. We sought to obtain further evidence by establishing and validating a radioligand binding assay for this receptor with (-)-[3H]-CGP 12177A ([-]-4-(3-tertiarybutylamino-2-hydroxypropoxy) benzimidazol-2-one) in rat atrium. We investigated (-)-[3H]-CGP 12177A for this purpose for two reasons, because it is a non-conventional partial agonist and also because it is a hydrophilic radioligand. 2. Increasing concentrations of (-)-[3H]-CGP 12177A, in the absence or presence of 20 microM (-)-CGP 12177A to define non-specific binding, resulted in a biphasic saturation isotherm. Low concentrations bound to beta1- and beta2-adrenoceptors (pKD 9.4+/-0.1, Bmax 26.9+/-3.1 fmol mg(-1) protein) and higher concentrations bound to the 'putative beta4-adrenoceptor' (pKD 7.5+/-0.1, Bmax 47.7+/-4.9 fmol mg(-1) protein). In other experiments designed to exclude beta1- and beta2-adrenoceptors, (-)-[3H]-CGP 12177A (1-200 nM) binding in the presence of 500 nM (-)-propranolol was also saturable (pKD 7.6+/-0.1, Bmax 50.8+/-7.4 fmol mg(-1) protein). 3. The non-conventional partial agonists (-)-CGP 12177A (pKi 7.3+/-0.2), (+/-)-cyanopindolol (pKi 7.6+/-0.2), [-]-pindolol (pK1 6.6+/-0.1) and (+/-)-carazolol (pKi 7.2+/-0.2) and the antagonist (-)-bupranolol (pKi 6.6+/-0.2), all competed for (-)-[3H]-CGP 12177A binding in the presence of 500 nM (-)-propranolol at the 'putative beta4-adrenoceptor', with affinities closely similar to potencies and affinities determined in organ bath studies. 4. The catecholamines competed with (-)-[3H]-CGP 12177A at the 'putative beta 4-adrenoceptor' in a stereoselective manner, (-)-noradrenaline (pKiH 6.3+/-0.3, pKiL 3.5+/-0.1), (-)-adrenaline (pKiH 6.5+/-0.2, pKiL 2.9+/-0.1), (-)-isoprenaline (pKiH 6.2+/-0.5, pKiL 3.4+/-0.1), (+)-isoprenaline (pKi< 1.7), (-)-RO363 ((-)-(1-(3,4-dimethoxyphenethylamino)-3-(3,4-dihydroxyphenoxy++ +)-2-propranol)oxalate, pKi 5.5+/-0.1). 5. The inclusion of guanosine 5-triphosphate (GTP 0.1 mM) had no effect on binding of (-)-CGP 12177A or (-)-isoprenaline to the 'putative beta4-adrenoceptor'. In competition binding studies, (-)-CGP 12177A competed with (-)-[3H]-CGP 12177A for one receptor state in the absence (pKi 7.3+/-0.2) or presence of GTP (pKi 7.3+/-0.2). (-)-Isoprenaline competed with (-)-[3H]-CGP 12177A for two states in the absence (pKiH 6.6+/-0.3, pKiL 3.5+/-0.1; % H 25+/-7) or presence of GTP (pKiH 6.2+/-0.5, pKiL 3.4+/-0.1; % H 37+/-6). In contrast, at beta1-adrenoceptors, GTP stabilized the low affinity state of the receptor for (-)-isoprenaline. 6. The specificity of binding to the 'putative beta 4-adrenoceptor' was tested with compounds active at other receptors. High concentrations of the beta 3-adrenoceptor agonists, BRL 37344 ((RR+SS)[4-[2-[[2-(3-chlorophenyl)-2-hydroxy-ethyl]amino]propyl]phenoxy]acetic acid, 6 microM), SR 58611A (ethyl{(7S)-7-[(2R)-2-(3-chlorophenyl)-2-hydroxyethylamino]-5,6,7,8-tetrahydronap htyl2-yloxy} acetate hydrochloride, 6 microM), ZD 2079 ((+/-)-1-phenyl-2-(2-4-carboxymethylphenoxy)-ethylamino)-ethan-1-ol, 60 microM), CL 316243 (disodium (R,R)-5-[2-[2-(3-chlorophenyl)-2-hydroxyethyl-amino]propyl]- 1,3-benzodioxole-2,2-dicarboxylate, 60 microM) and antagonist SR 59230A (3-(2-ethylphenoxy)-1-[(1S)-1,2,3,4-tetrahydronaphth-1-ylamino]-2S-2-propanol oxalate, 6 microM) caused less than 22% inhibition of (-)[3H]-CGP 12177A binding in the presence of 500 nM (-)propranolol. Histamine (1mM), atropine (1 microM), phentolamine (10 microM), 5-HT (100 microM) and the 5-HT4 receptor antagonist SB 207710 ((1-butyl-4-piperidinyl)-methyl 8-amino-7-iodo-1,4-benzodioxan-5-carboxylate, 10nM) caused less than 26% inhibition of binding. 7.Non-conventional partial agonists, the antagonist (-)bupranolol and catecholamines all competed for (-)[3H]-CGP 12177A binding in the absence of (-)propranolol at beta1-adrenoceptors, with affinities (pKi) ranging from 1.6-3.6 log orders greater than at the 'putative beta 4-adrenoceptor'. 8.We have established and validated a radioligand binding assay in rat atrium for the 'putative beta 4-adrenoceptor' which is distinct from beta1-, beta2- and beta 3-adrenoceptors. The stereoselective interaction with the catecholamines provides further support for the classification of the receptor as 'putative beta 4-adrenoceptor'.

Differences between the third cardiac beta-adrenoceptor and the colonic beta 3-adrenoceptor in the rat.[Pubmed:8864547]

Br J Pharmacol. 1996 Aug;118(8):2085-98.

1. The heart of several species including man contains atypical beta-adrenoceptors, in addition to coexisting beta 1- and beta 2-adrenoceptors. We now asked the question whether or not the third cardiac beta-adrenoceptor is identical to the putative beta 3-adrenoceptor. We compared the properties of the third cardiac beta-adrenoceptor with those of beta 3-adrenoceptors in isolated tissues of the rat. To study the third cardiac beta-adrenoceptor we used spontaneously beating right atria, paced left atria and paced left ventricular papillary muscles. As a likely model for putative beta 3-adrenoceptors we studied atypical beta-adrenoceptors of the colonic longitudinal muscle precontracted with 30 mM KCl. We used beta 3-adrenoceptor-selective agonists, antagonists and non-conventional partial agonists (ie high-affinity blockers of both beta 1- and beta 2-adrenoceptors know to exert also stimulant effects through beta 3-adrenoceptors). 2. The non-conventional partial agonist (-)-CGP 12177 caused positive chronotropic effects in right atria (pD2 = 7.3) and positive inotropic effects in left atria (pD2 = 7.5). The stimulant effects of (-)-CGP 12177 were resistant to blockade by 200 nM-2 microM (-)-propranolol and 3 microM ICI 118551 (a beta 2-selective antagonist) but antagonized by 1 microM (-)-bupranolol (pKB = 6.4-6.8), 3 microM CGP 20712A (a beta 1-selective antagonist) (pKB = 6.3-6.4) and 6.6 microM SR 59230A (a beta 3-selective antagonist, pKB = 5.1-5.4). 3. The non-conventional partial agonist cyanopindolol caused positive chronotropic effects in right atria (pD2 = 7.7) and positive inotropic effects in left atria (pD2 = 7.1). The stimulant effects of cyanopindolol were resistant to blockade by 200 nM (-)-propranolol but antagonized by 1 microM (-)-bupranolol (pKB = 6.8-7.1). 4. Neither (-)-CGP 12177 nor cyanopindolol caused stimulant effects in papillary muscles at concentrations between 0.2 nM and 20 microM. 5. In the presence of 200 nM (-)-propranolol the beta 3-adrenoceptor-selective agonists BRL 37344 (6 microM), SR 58611A (6 microM), ZD 2079 (60 microM) and CL 316243 (60 microM) did not cause stimulant effects or modify the potency and efficacy of the effects of (-)-CGP 12177 in right and left atria. The combination of 2 microM (-)-propranolol and 2 microM (-)-noradrenaline did not modify the chronotropic potency and efficacy of (-)-CGP 12177 compared to the potency and efficacy in the presence of 2 microM (-)-propranolol alone. 6. (-)-CGP 12177 relaxed the colon with a pD2 of 6.9 and a maximum effect of 55% compared to (-)-isoprenaline. The relaxant effects of (-)-CGP 12177 were resistant to blockade by 200 nM (-)-propranolol, 3 microM CGP 20712A, 3 microM ICI 118551 but blocked by 2 microM (-)-propranolol (pKB = 6.0), 1 microM (-)-bupranolol (pKB = 6.4) and 3 microM SR 59230A (pKB = 6.3). In the presence of 200 nM (-)-propranolol, (-)-CGP 12177 (20 microM) antagonized surmountably the relaxant effects of BRL 37344 (pKP = 7.3) (-)-noradrenaline (pKP = 7.0); and CL 316243 (pKP = 7.0). 7. Cyanopindolol in the presence of 200 nM (-)-propranolol relaxed the colon with a pD2 of 7.0 and a maximum effect of 40% compared to (-)-isoprenaline. As expected from a partial agonist, cyanopindolol antagonized the relaxant effects of both BRL 37344 and CL 316243 with a pKP = 7.6 and (-)-noradrenaline with a pKP = 7.4. 8. The following beta 3-adrenoceptor-selective agonists were potent colonic relaxants (pD2 values between parentheses): BRL 37344 (9.1), ZD 2079 (7.0), CL 316243 (9.0) and SR 58611A (8.2). The relaxant effects of these agonists were only marginally affected by 200 nM (-)-propranolol, not blocked by 3 microM CGP 20712A or 3 microM ICI 118551, and blocked by SR 59230A 3 microM (pKB = 6.9-7.5), 1 microM (-)-bupranolol (pKB = 6.2-6.4) and 2 microM (-)-propranolol (pKB = 6.3-6.5). 9...

Effects of several putative beta 3-adrenoceptor agonists on lipolysis in human omental adipocytes.[Pubmed:8696421]

Int J Obes Relat Metab Disord. 1996 May;20(5):428-34.

BACKGROUND: Atypical beta 3-adrenoceptor agonists have attained an increasing interest as potential drugs against obesity and diabetes. However, their pharmacological actions on the native, human beta 3-adrenoceptor are not well defined. DESIGN: In the present study, the lipolytic effects of several putative beta 3-adrenoceptor agonists were investigated in human omental adipocytes. RESULTS: CL 316 243 and CGP 12177 had selective partial beta 3-agonist effects (pD2 about 4 and 8, respectively); the latter drug is a beta 1-/beta 2-adrenoceptor blocker in addition to its beta 3-adrenoceptor agonist activity. BRL 37344 and SM 11044 were also partial agonists, but with significant beta 1- and/or beta 2-adrenoceptor agonist properties. Bucindolol, ZD 2079, ICI D7114 and SR 58611A were ineffective as lipolytic drugs. In addition, ICI D7114 was a non-selective beta 1-/beta 2-/beta 3-adrenoceptor antagonist in human adipocytes. CONCLUSION: None of the beta 3-adrenoceptor agonists tested is an ideal drug for therapeutic use in man (i.e. regarded as a selective and full agonist with high receptor potency). Only CL 316 243 may have a potential therapeutic role, although the potency is very low. CGP 12177 is useful as a reference substance for human in vitro studies.

Mediation of the positive chronotropic effect of CGP 12177 and cyanopindolol in the pithed rat by atypical beta-adrenoceptors, different from beta 3-adrenoceptors.[Pubmed:8851515]

Br J Pharmacol. 1996 Mar;117(5):943-9.

1. The influence of beta 1-, beta 2-, and beta 3-adrenoceptor agonists and of CGP 12177 and cyanopindolol on heart rate and diastolic blood pressure was studied in the pithed rat. 2. The beta 1-adrenoceptor agonist, prenalterol, increased heart rate and the beta 2-adrenoceptor agonist, fenoterol, caused a fall in blood pressure. The effect of prenalterol was antagonized by the beta 1-adrenoceptor antagonist, CGP 20712 0.1 mumol kg-1 and the action of fenoterol was attenuated by the beta 2-adrenoceptor antagonist, ICI 118551 0.1 mumol kg-1. Both effects were markedly diminished by the non-selective beta-adrenoceptor antagonist, bupranolol 0.1 mumol kg-1. 3. The non-selective beta-adrenoceptor agonist, isoprenaline, three beta 3-agonists as well as CGP 12177 and cyanopindolol elicited a positive chronotropic effect, exhibiting the following pED delta 60 values (negative log values of the doses increasing heart rate by 60 beats min-1): isoprenaline 10.4, CGP 12177 8.3, cyanopindolol 7.2, BRL 37344 6.9, ZD 2079 5.2 and CL 316243 < 5. 4. CGP 20712 0.1 mumol kg-1, given together with ICI 118551 0.1 mumol kg-1, markedly attenuated the positive chronotropic effect of isoprenaline, BRL 37344, ZD 2079 and CL 316243 without affecting the increase in heart rate produced by CGP 12177 and cyanopindolol. 5. The positive chronotropic effect of CGP 12177 and cyanopindolol was attenuated by CGP 20712, 1 and 10 mumol kg-1 and bupranolol, 10 mumol kg-1 but was not affected by ICI 118551, 10 mumol kg-1. The effect of CGP 12177 was also not changed by BRL 37344 1 mumol kg-1, ZD 2079 10 mumol kg-1, CL 316243 10 mumol kg-1, the alpha 1-adrenoceptor antagonist, prazosin 1 mumol kg-1 and the 5-hydroxytryptamine 5-HT2A receptor antagonist, ketanserin 3 mumol kg-1. 6. CGP 12177 0.002 mumol kg-1 and cyanopindolol 0.003 mumol kg-1 shifted to the right the dose-response curve of prenalterol for its positive chronotropic effect. The -log values of the doses causing a twofold shift to the right were 9.6 and 9.5, respectively. 7. Isoprenaline 0.00001-0.001 mumol kg-1, BRL 37344 0.01-1 mumol kg-1 and CGP 12177 0.1 mumol kg-1 caused a fall in diastolic blood pressure which was markedly attenuated by combined administration of CGP 20712 and ICI 118551, 0.1 mumol kg-1 each. 8. CGP 12177 0.01 and 0.1 mumol kg-1 and cyanopindolol 1 mumol kg-1 elicited an increase in diastolic blood pressure. CGP 20712, ICI 118551, bupranolol and, in the case of CGP 12177, also BRL 37344, ZD 2079, CL 316243, prazosin and ketanserin did not influence this effect. 9. In conclusion, the positive chronotropic effect of CGP 12177 and cyanopindolol is not mediated via beta 1-, beta 2-, beta 3-, alpha 1-adrenoceptors or 5-HT2A receptors. This effect may involve atypical beta-adrenoceptors, similar or identical to those described by Kaumann (1989) in isolated heart preparations.

Pharmacological characteristics and species-related variations of beta 3-adrenergic receptors.[Pubmed:7557816]

Fundam Clin Pharmacol. 1995;9(3):211-8.

Beta-adrenergic receptors (beta-AR) belong to the large multigenic family of receptors coupled to GTP-binding proteins. Three subtypes have been identified: beta 1-, beta 2- and beta 3-AR. Much of the work delineating the precise pharmacological comparison of the three beta-ARs has come from investigations with stably transfected Chinese hamster ovary cells (CHO cells). This review discusses the structure and function of beta 3-AR in various species and presents new findings on a number of beta 3-AR ligands including carazolol, tertatolol and CL 316,243 which were found to be selective and potent beta 3-AR agonists and ZD 2079 and salmeterol which appear to display full but non-subtype selective agonistic activity. Species-related variations of the beta 3-AR pharmacology have been shown for propranolol and bupranolol. With the ongoing characterization of the beta 3-AR at the molecular and cellular level, and with the advent of computer-assisted molecular modelling to aid in the determination of the three-dimensional structure of the receptor, it is thought that novel beta 3-AR compounds will become available with improved selectivity and potency.

Role of endothelium/nitric oxide in atypical beta-adrenoceptor-mediated relaxation in rat isolated aorta.[Pubmed:10854841]

Eur J Pharmacol. 2000 Jun 16;398(2):285-96.

The role of endothelium in the modulation of classical and atypical beta-adrenoceptor-mediated vasorelaxation was investigated in ring preparations of rat isolated thoracic aorta. Rings were pre-constricted with a sub-maximal concentration of noradrenaline (1 microM) and relaxant responses to cumulative concentrations of beta-adrenoceptor agonists obtained. Endothelium removal or pretreatment with N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM) or 1H-[1,2,4] oxadiazolol[4,3,-a] quinoxalin-1-one (ODQ, 10 microM) significantly reduced the relaxant effects of isoprenaline, but had less effect on relaxant responses to the atypical beta-adrenoceptor agonist, (+/-)-4-(3-t-butylamino-2-hydroxypropoxy)-benzimidazol-2-one hydrochloride (CGP 12177A). Sodium nitroprusside (3 nM) shifted the isoprenaline concentration-response curve to the left and restored the attenuated responses in the presence of L-NAME back to control levels. Sodium nitroprusside had little effect on the CGP 12177A concentration-response curve. The results show that the endothelium/nitric oxide (NO) pathway modulates beta-adrenoceptor-mediated vasorelaxation in rat aorta and that classical beta-adrenoceptors are modulated to a greater extent than atypical beta-adrenoceptors.