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Adrenoceptor Pharmacology

Adrenoceptor Pharmacology

ADRENOCEPTOR

Emma Robinson and Alan Hudson within each group have now been cloned and Unit pharmacologically characterised. Thea1- adrenoceptor Department of Pharmacology subtypes have been classified as theaa1A , 1B and a 1D - School of Medical Sciences adrenoceptor and thea2 -adrenoceptors have been University of Bristol, University Walk classified as thea2A (a2D species variation of the human BS8 1TD, UK aa2A),2B anda -adrenoceptor.

Dr Alan Hudson is Head of Preclinical Research b-Adrenoceptors are also heterogeneous in nature and for the Psychopharmacology Unit, Emma were again initially subdivided intobb - and - Robinson is a Teaching Assistant in the 12 adrenoceptors, on the basis of the relative potencies of Department of Pharmacology a series of inin vitro and in vivo systems.3 Subsequently theb -adrenoceptors have Introduction been classified using functional studies, binding and genetic techniques. Theb -adrenoceptor

Adrenoceptors are membrane bound receptors located family is subdivided into three distinct subtypes, the b1- throughout the body on neuronal and non-neuronal andb2- adrenoceptors and the atypicalb3 - tissues where they mediate a diverse range of adrenoceptor.4 There is an additionalb -adrenoceptor responses to the endogenous catecholamines subtype which has been identified in cardiac tissue and noradrenaline and . The adrenoceptor family is a putative, atypical subtype classified as theb4 - was first divided into two subtypes, theab - and - adrenoceptor.5 adrenoceptors as determined by pharmacological studies in isolated tissue.1 A quarter of a century later, a -Adrenoceptors thea -adrenoceptors were further subdivided based on 1 their anatomical location, witha -adrenoceptors located a1-Adrenoceptor subtypes on peripheral sympathetic nerve terminals designated Subdivision of thea1- adrenoceptors has been a2-adrenoceptors and those located post-synaptically facilitated by both pharmacological and molecular 2 designateda1 -adrenoceptors. This anatomical biological techniques.6 The initial classification of the classification rapidly gave way to the identification of aa11B-adrenoceptors asa1A and -subtypes was pharmacological differences between thea - determined from differences in the binding adrenoceptors, notably the ability of and characteristics of the competitive antagonist WB 4101 to act asa2- adrenoceptor antagonists. and the site-directed alkylating agent Subsequent studies using pharmacological and chloroethylclonidine (CEC). From radioligand binding molecular biological techniques have further studies it was determined that thea1A -subtype has a subdivided thea -adrenoceptor family; three subtypes high affinity for WB 4101 and is CEC-insensitive, whilst

Table 1.a1 -Adrenoceptor characteristics

Receptor typea1A -Adrenoceptoraa1B -Adrenoceptor 1D -Adrenoceptor

Selective agonistsoxymetazoline, A61603 none none

Non-subtype selectivecirazoline , M-6434 , , M-6434 , cirazoline, M-6434, , , methoxamine, phenylephrine, methoxamine, phenylephrine,

Selective antagonistsRS 17053, WB 4101, CEC (irreversible) BMY 7378 , SKF105854, (S)-(+)-, CEC (irreversible) 5-methylurapidil, SNAP5089, Rec152739, SB216469, Ro700004, KMD3213

Non-subtype selective , corynanthine, prazosin corynanthine, prazosin antagonists

2+ 2+ Transduction activates Gp/q ,­­ PI turnover, [Ca ]i.c. , activates voltage-gated Ca channels mechanism

Physiological function smooth muscle contraction, smooth muscle contraction smooth muscle contraction myocardial contraction

(bold text denotes compounds available from Tocris)

Tocris Cookson Ltd., UK Tocris Cookson Inc., USA Tel: + 44 (0)117 982 6551 Toll Free Tel: (800) 421-3701 Tel: (636) 207-7651 Fax: + 44 (0)117 982 6552 Toll Free Fax: (800) 483-1993 Fax: (636) 207-7683 e-mail: [email protected] e-mail: [email protected] e-mail: [email protected] 16 thea1B -subtype exhibits a low affinity for WB 4101 but is adrenoceptor mRNA in the hippocampus and cortex. sensitive to CEC (Table 1). These characteristics were Peripherala1 -adrenoceptors are located on both also shown in a variety of tissue preparations vascular and non-vascular smooth muscle where confirming the presence of functional receptor activation of the receptor results in contraction.17 On 7 subtypes. In addition, three different cDNAs which vascular smooth muscle thea1 -adrenoceptors are coded fora1 -subtypes were isolated. These have since located intrasynaptically where they mediate the been characterised and are believed to code for three response to endogenous release. functionalaaa11A1B -adrenoceptors: the and -subtypes They are also located on the heart where they mediate a positive inotropic effect and on the liver where they as described above and a third subtype, thea1D which has a low affinity for in contrast to the activate glycogen phosphorylation. With the availability of subtype selective compounds thea -subtype has a1A-subtype, and is only partially sensitive to CEC, thus 1A been shown to be responsible for the contraction of vas making it pharmacologically distinct from the a1B receptor.8 The putativea -adrenoceptor shows similar deferens smooth muscle. in some 1L 18 characteristics to theaa - and -adrenoceptor but blood vessels has been shown to bea1B -mediated 1A 1D 16, 19 exhibits a low affinity for prazosin and, as yet the gene and contraction of the rat aorta isa1D -mediated. has not been identified.9 Compounds displaying a high a -Adrenoceptors affinity for thea1 -adrenoceptor subtype compared to 2 other receptors include the agonists cirazoline and M- 6434 and antagonists such as prazosin and HEAT. a2-Adrenoceptor subtypes Thea -adrenoceptors are located on both pre and post These twoa1 -selective antagonists are also used as 2 radioligands for investigating the binding synaptic neurones where they mediate an inhibitory role in the central and peripheral nervous system.20 The characteristics ofa1 -adrenoceptors. However, heterogeneous nature of thea -adrenoceptor was first following the initial characterisation of thea1 - 2 adrenoceptor subtypes subtype selective agonists and determined from the different pharmacological profiles antagonists are now being developed which include the of the receptor between species and subsequent a -selective agonists A6160310 and oxymetazoline, 4 studies have revealed the presence of different 1A subtypes within the same tissue. Thus, on the basis of and theaa -selective antagonist RS17053.11 The - 1A 1B radioligand binding profiles, amino acid sequence and adrenoceptor subtype has a higher affinity for CEC than chromosomal location, four distinct subtypes of thea - thea -subtype but CEC also exhibits a similar affinity 2 1A adrenoceptor have been characterised.21 Thesea - for thea -subtype. However, antagonists selective for 2 1D adrenoceptor subtypes,aaa , , and a are found thea -subtype such as BMY7378 and SKF105854 are 2A 2B 2C 2D 1D in a variety of species and tissues and have been now available.12, 13 characterised using tissue and cell lines expressing Signal transduction mechanism only one subtype. Thea2D -subtype exhibits a distinct pharmacological profile but, from the sequence Thea -adrenoceptors mediate their response via G- 1 homology is believed to be a species variation of the protein coupled receptors through a G /G mechanism. pq 22 All the subtypes are coupled to phospholipase C and a2A-subtype and is not recognised as separate. Although selective compounds are now being activation of the receptor results in the production of IP3 and DAG. The production of these second messengers developed to differentiate between thea2 -adrenoceptor results in an activation of both voltage dependent and subtypes there is no available that is highly independent Ca2+ channels as well as stimulation of selective in functional studies for thea2 -adrenoceptor subtypes. Characterisation is based on the affinity of a protein kinase C, phospholipase A2 and D, arachidonic acid release and cyclic AMP formation.14, 15 range of compounds which exhibit different affinities for the subtypes (Table 2). Oxymetazoline displays a

Location and function higher affinity for thea2A/D -subtype whilst prazosin Thea1 -adrenoceptors are located in the central and exhibits a higher affinity for theaa2B -subtype. The 2C - peripheral nervous system. In the CNS they are subtype has a high affinity for prazosin and low affinity predominantly located post-synaptically where they for oxymetazoline, characteristic of thea2B - mediate an excitatory role. Following cloning of thea1 - adrenoceptor subtype but the affinity for yohimbine is adrenoceptor subtypes, mRNA studies have showna1 - characteristic of thea2A -subtype. The antagonist MK

Table 2.a2 -Adrenoceptor characteristics

Receptor typea2A -Adrenoceptoraa2B -Adrenoceptor 2C -Adrenoceptor (previous name) (aaa2A , 2D , 2- C10, RG20) ( a 2 -C2, RNG) ( a 2 -C4)

Selective agonistsoxymetazoline (partial ), none none

Non-subtype selective UK 14,304 UK 14,304 UK 14,304 agonists Clonidine Clonidine

Selective antagonistsBRL 44408 , BRL 48962 ARC 239 , rauwolscine , MK 912

Non-subtype selectiveRS 79948, yohimbine , RS 79948, yohimbine , RS 79948, yohimbine , antagonists RS 15385, RX821002, RS 15385, RX821002, RS 15385, RX821002, SKF 86466, MK-912, SKF 86466, MK-912, SKF 86466, MK-912, rauwolscine,, prazosin rauwolscine prazosin rauwolscine , prazosin

2+ Transduction activates Gi/o ,inhibits adenylyl cyclase,¯ cAMP, inhibits voltage-gated Ca channels, mechanism activates Ca2+ -dependent K+ channels

Physiological function hypotension, sedation, vasoconstriction not determined analgesia, anaesthesia, inhibition of neurotransmitter release

(bold text denotes compounds available from Tocris)

2 912 has been shown to have a partial selectivity for the Furthermore, the sedative properties ofa2 -agonists, 23 a2C-adrenoceptor subtype in binding studies. mediated by somatodendritic autoreceptors on the Although these ligands can be used for radioligand locus coeruleus, have resulted in the development of binding studies to determine the receptor subtype a2-adrenoceptor agonists such as as present in a tissue, the selectivity is not sufficient for veterinary sedatives and anaesthetics. Thea2 -agonists characterisation of the function of receptor subtypes in also have the advantage of being analgesic, a response vivo. Subtype selective compounds which have been mediated bya2 -adrenoceptors in the spinal cord. Other developed include the antagonists BRL 4408 and BRL central effects ofa -adrenoceptors include the 24 2 48962, selective for thea2A -subtype, ARC 239 and regulation of blood pressure, hypothermia, pupil 25, 26 imiloxan, selective for thea2B -subtype and diameter and a role in cognitive function. Peripheral rauwolscine which shows a 10-20 fold selectivity for the functions include contraction of vascular smooth aa-subtype.27 Highly selective -adrenoceptor 2C 2 muscle, inhibition of lypolysis througha2 - compounds such as the agonists UK 14, 304 andp - adrenoceptors located on fat cells and aminoclonidine, and antagonists RX821002 and hyperpolarisation of sympathetic ganglia. RS79948 exhibit a high affinity for thea2 -adrenoceptor compared to other receptors such as thea1 - b-Adrenoceptor adrenoceptor. b-Adrenoceptor subtypes Signal transduction mechanism Thebb -adrenoceptors were first subdivided into1 - and Thea -adrenoceptors are part of the large family of G- 2 b2-adrenoceptors following comparison of the rank protein coupled receptors and mediate their functions order of of various agonists.3 The through a variety of G-proteins including Gio /G . All the b1-adrenoceptor is predominant in the heart and on subtypes have been shown to be negatively coupled to adipose tissue and displays equal affinity for adrenaline adenylate cyclase and mediate an inhibitory effect and noradrenaline. In contrast, theb -adrenoceptor is through the inhibition of cyclic AMP production. In 2 predominant on vascular, uterine and airway smooth addition there is now evidence linking thea2 - muscle and exhibits a higher selectivity for 2+ adrenoceptor to stimulation of Ca influx and also noradrenaline than adrenaline.30 Following the activation of K+ channels, phospholipase A and Na++ /H 2 identification of these twob -adrenoceptor subtypes, exchange.28 compounds selective for the subtypes have been developed (Table 3). These include the selectiveb - Location and function 1 31 adrenoceptor agonist , and the selectiveb2 - a2-Adrenoceptors are found in both the central and peripheral nervous system, and located both pre and adrenoceptor agonists , , clenbuterol32 and . 33 Selective antagonists for post synaptically.20 Functional studies to determine the role of the different receptors based on anatomical theb1 -adrenoceptor include CGP20712A, , location has been achieved by the use of selective and betaxolol34, 35 whilst ICI118551 is a 36 agonists and antagonists and also by the use of selectiveb2 -adrenoceptor antagonist. ICI118551 is lesioning experiments whereby the pre-synaptic nerve also available as a radioligand for direct labelling ofb2 - terminals are destroyed with for example the toxin DSP- adrenoceptors.37 4.29 In the CNS these receptors play an important role in regulating neurotransmitter release through The classification ofb -adrenoceptors is not limited tob1 - autoreceptors located on noradrenergic nerve andb2 -adrenoceptors. Characterisation ofb - terminals and heteroreceptors located on other adrenoceptor mediated responses resulted in evidence neurotransmitter terminals. Their importance in for a further atypical subtype which is insensitive to regulating the release of both noradrenaline and typicalb -adrenoceptor antagonists.38, 39 This subtype has resulted in the investigation and has since been classified as theb3 -adrenoceptor. development ofa -antagonists such as for 2 Selective agonists for theb3 -adrenoceptor include use in the treatment of depression. They also mediate BRL3734440 and ZD7114 41 while, SR59230A is a central cardiovascular responses anda2 -agonists such selective antagonist.42 Pharmacological evidence also as clonidine cause hypotension and bradycardia. suggests the presence of another atypicalb -

Table 3.b -Adrenoceptor characteristics

Receptor typebbb123 -Adrenoceptor -Adrenoceptor -Adrenoceptor b 4 -Adrenoceptor

Selective agonistsxamoterol , , BRL 37344 , none denopamineprocaterol , ZD 7114 , CGP12177 , salbutamol, CL316243 salmeterol, , ,

Selectivebetaxolol, bisoprolol , ICI-118,551 SR59230A none antagonistsatenolol , ( CGP20712A >CGP20712A)

Radioligands [125 I]-,[3 H]-ICI-118,551 [I125 ]-iodocyanopindolol, [H 3 ]-CGP12177 [H3 ]-CGP12177 [H3 ]-CGP12177

Transduction­­­ adenylyl cyclase adenylyl cyclase adenylyl cyclase ­ cAMP levels,

mechanism (via Gs ) (viaGs ) or¯ adenylyl cyclase stimulation of ­¯/ adenylyl cyclase cAMP-dependent protein kinase

(viaGs )

Physiological­ heart rate and force smooth muscle lipolysis,­ heart rate and function relaxation cardioinhibition force e.g. bronchodilation

(bold text denotes compounds available from Tocris)

3 adrenoceptor subtype, theb4 -adrenoceptor which is compounds has long been established as an effective localised in cardiac tissue.5 Although there are no therapy for the treatment of asthma and other bronchospastic conditions; salbutamol and salmeterol selective compounds for this subtype, theb4 - adrenoceptor has a low affinity for adrenaline and are examples of such in current clinical use. Beta noradrenaline but is blocked by theb -adrenoceptor blockers are used in the treatment of pectoris antagonists bupranolol and CGP20712A.43, 44 and cardiac arrhythmias; they are used both as a treatment for acute congestive (e.g. Signal transduction mechanism ), and for long-term management of Theba -adrenoceptors, like the -adrenoceptors, are patients who survive myocardial infarction. In addition, coupled to G-proteins and subsequent intracellular b-adrenoceptor antagonists such as and 45 bisoprolol have been utilised as effective second messenger systems. Theb1 -adrenoceptor is positively coupled to adenylate cyclase via activation of antihypertensives for several decades. Beta-blockers have also been used for management of the G G-proteins as are thebb - and - adrenoceptors. s23withdrawal syndrome, anxiety disorders, migraine However, activation of thebb - and - adrenoceptors 23 prophylaxis, hyperthyroidism and tremor, and can also results in stimulation or stimulation and inhibition of be applied topically to treat ocular hypertension and adenylate cyclase. Activation of theb -adrenoceptor 4 glaucoma. Conversely, the actions which result fromb - results in increased cAMP and stimulation of cAMP- adrenoceptor blockade can also be disadvantageous; dependent protein kinase. There is also evidence to heart failure, heart-block and bronchospasm being suggestb -adrenoceptors are linked via a stimulatory G- unwanted and serious side-effects.a -Adrenoceptor 2+ 46 protein to voltage-gated Ca channels. ligands can provide an effective therapy for hypertension;a -adrenoceptor antagonists such as Location and function 1 and prazosin are widely employed as Thebb - and -adrenoceptors have distinct patterns of 12 antihypertensive agents, as is thea -adrenoceptor distribution in the CNS determined using in situ 2 agonist clonidine. The sedative effects of clonidine and hybridisation studies.47 b -Adrenoceptors are found in 1 othera -adrenoceptor agonists make them useful as high density in the striatum and a selective decrease in 2 adjuncts to general anaesthetics; and the number of these receptors has been observed in are commonly used as such in Huntington’s chorea.48 Activation ofb -adrenoceptors 1 veterinary .a -adrenoceptor antagonists such increases the force and rate of the heart whilstb - 1 2 as prazosin and are also thought to be adrenoceptor activation results in vasodilatation and effective in the management of benign prostatic bronchodilation. Therefore drugs acting onb - hypertrophy although the cardiovascular side-effects adrenoceptors located on cardiac muscle, airway associated with the blockade of vasculara1 - muscle and fat cells are of particular interest for their adrenoceptors can be problematic. use in the treatment of cardiovascular disease, asthma and obesity. The atypicalb3 -adrenoceptor is expressed As is apparent, adrenergic ligands have a diverse range predominantly in adipose tissue where it is proposed to of clinical applications. In addition to the established be involved in regulating noradrenaline induced therapeutic uses for these drugs, there is an interest in changes in energy metabolism and thermogenesis. potential new applications which include the use of a2 Therefore,b3 -adrenoceptor agonists are likely to be of adrenergic compounds as analgesics and the use of benefit in the treatment of obesity.5 selectiveb3 -adrenoceptor agonists as anti-obesity agents. There is also a need for improvement of the therapeutic profiles of the adrenergic compounds in Clinical Application and Future Directions common clinical use to minimise the side-effects often seen, and these may well follow on from the continuing Many adrenergic compounds are currently in development of more subtype selective adrenergic widespread clinical use, and are used to treat a range of compounds and a clearer understanding of the disorders. The inhalation ofb2 -adrenoceptor selective functional roles of the individual subtypes within the two adrenoceptor families.

References 26.Michel et al (1990) Br.J.Pharmacol.99 560. 27.Hieble et al (1995) J.Med.Chem.38 3415. 1.Ahlquist (1948) Am.J.Physiol.153 586. 28.Bylund et al (1995) Ann.N.Y.Acad.Sci.763 1. 2.Langer (1974) Biochem.Pharmacol.23 1793. 29.Heal et al (1995) Eur.J.Pharmacol.277 215. 3.Lands et al (1967) Nature214 597. 30.Arch et al (1995) Pharmacol.Comm.6 223. 4.Strosberg and Pietri-Rouxel (1996) TiPS.17 373. 31.Nuttall and Snow (1982) Br.J.Pharmacol.77 381. 5.Kauman (1997) TiPS.18 70. 32.Strosberg and Pietri-Rouxel (1996) TiPS.17 373. 6.Minneman and Esbenshade (1994) 33.Yoshizaki et al (1977) J.Med.Chem.20 1103. Ann.Rev.Pharmacol.Toxicol.34 117. 34.Satoh et al (1993) Br.J.Pharmacol.108 484. 7.Morrow and Creese (1986) Mol.Pharmacol.29 321. 35.Kauman and Lemoine (1985) Naunyn- 8.Hieble et al (1995) Pharmacol.Rev.47 267. Schmied.Arch.Pharmacol.331 27. 9.Ford et al (1994) TiPS.15 167. 36.Bilski et al (1983) J.Cardiovasc.Pharmacol.5 430. 10.Buckner et al (1995) Eur.J.Pharmacol.297 241. 37.Lemoine et al (1985) Naunyn-Schmied.Arch.Pharmacol. 11.Ford et al (1995) Mol.Pharmacol.49 209. 331 40. 12.Piascik et al (1995) J.Pharmacol.Exp.Ther.275 1583. 38.Arch et al (1984) Nature309 163. 13.Hieble et al (1995) Pharmacol.Comm.6 91. 39.Bond and Clarke (1988) Br.J.Pharmacol.95 723. 14.Harrison et al (1991) TiPS.12 62. 40.Oshita et al (1997) Br.J.Pharmacol.122 1720. 15.Berridge and Irvine (1989) Nature341 197. 41.Savontaus et al (1998) Eur.J.Pharmacol.347 265. 16.Bylund (1992) FASEB J.6 832. 41.Manara et al (1995) Br.J.Pharmacol.117 1374. 17.Aboud et al (1993) Br.J.Pharmacol.109 80. 43.Sarsero et al (1998) Br.J.Pharmacol.123 371. 18.Muramatsu et al (1991) Br.J.Pharmacol.99 197. 44.Galitzky et al (1997) Br.J.Pharmacol.122 1244. 19.Ruffolo and Hieble (1994) Pharmacol.Ther.61 1. 45.Stadet (1991) In: Molecular Biology, Biochemistry and 20.French (1995) Pharmacol.Ther.68 175. Pharmacology. Ed. R. R. Ruffolo p 67. 21.MacKinnon et al (1994) TiPS.15 119. 46.Bylund et al (1994) Pharmacol.Rev.46 121. 22.Simonneaux et al (1991) Mol.Pharmacol.40 235. 47.Nicholas et al (1996) TiPS.17 245. 23.Uhlen et al (1997) Brain Res.770 261. 48.Waeber et al (1991) Synapse8 270. 24.Beeley et al (1995) Bioorg.Med.Chem.Lett.3 1693. 25.Bylund et al (1988) J.Pharmacol.Exp.Ther.245 600.

4 Available from Tocris

a1-Adrenoceptor Selective Compounds

Agonists

1052 A 61603...... a1A agonist 0888 Cirazoline ...... Selectivea1 agonist 0461 M-6434...... a1 agonist 1142 Oxymetazoline ...... a1A agonist

Antagonists

1006 BMY 7378 ...... Selectivea1D antagonist, 5-HT 1A 1143 Corynanthine...... a1 antagonist 0535 HEAT...... Highly selectivea1 antagonist 0545 ...... a1 antagonist. Also NMDA antagonist 0661 2-[[4-(2-Methoxyphenyl)piperazin-1-yl] ...... Potent, selectivea1 antagonist methyl]-6-methyl-2,3-dihydroimidazo ands2 ligand [1,2-c]-quinazolin-5(6H)-one

0597 ...... a1 antagonist 1124 (R)-(-)-Niguldipine ...... Less active enantiomer of (1123) 2+ 1123 (S)-(+)-Niguldipine...... a1 antagonist, L-type Ca 0627 2-[(4-Phenylpiperazin-1-yl)methyl]-2,3-...... Potent, selectivea1 antagonist dihydroimidazo[1,2c]quinazolin-5(6H)-one

0623 Prazosin ...... a1 antagonist. MT3 antagonist 0985 RS 17053 ...... a1A antagonist 0946 WB 4101 ...... a1A antagonist

General

0451 3-[2-[4-(2-Chlorophenyl)piperazin-1-yl] ...... a1 ligand ands2 ligand ethyl]-pyrimido[5,4-b]indole-2,4-dione

0580 3-[2-[4-(2-Methoxyphenyl)piperazin-1-yl] ...... a1 ligand ethyl]-1,5-dimethylpyrimido[5,4-b]indole- 2,4-dione

0581 3-[2-[4-(2-Methoxyphenyl)piperazin-1-yl] ...... a1 ligand ethyl]-pyrimido[5,4-b]indole-2,4-dione

a2-Adrenoceptor Selective Compounds

Agonists

0690 Clonidine ...... a2 agonist. Also imidazoline I1 ligand 0885 ...... a2 agonist. Also I2 selective ligand 1030 Guanfacine...... a2A agonist 1142 Oxymetazoline ...... a2A partial agonist 0790 ...... a2 agonist. Also imidazoline I1 ligand 0425 UK 14,304 ...... a2 agonist

Antagonists

0928 ARC 239...... a2B antagonist 1133 BRL 44408 ...... Selectivea2B antagonist 0986 Imiloxan...... Highly selectivea2B antagonist 0891 Rauwolscine...... a2 antagonist 0987 RS 79948 ...... Potent, selectivea2 antagonist 0631 ...... Potenta2 ligand 1127 Yohimbine ...... a2 -selective antagonist

General

0842 ...... a2 ligand. Also imidazoline ligand

Generala -Adrenoceptor Compounds

0474 Dihydroergocristine ...... Partiala agonist. Non selective 0475 ...... Partiala agonist. Non selective 0604 ...... a antagonist

b1-Adrenoceptor Selective Compounds

0387 (±)-Atenolol...... b1 antagonist 0392 R(+)-Atenolol...... Inactive isomer 0393 S(-)-Atenolol...... Active isomer

0906 Betaxolol ...... Selectiveb1 antagonist 0914 Bisoprolol ...... b1 antagonist

5 b1-Adrenoceptor Selective Compounds continued

0831 Practolol ...... b1 antagonist 0649 (S)-...... b1 antagonist 0950 Xamoterol...... b1 selective partial agonist

b2-Adrenoceptor Selective Compounds

0688 Clenbuterol...... b2 agonist 0821 ICI-118,551...... Very selectiveb2 antagonist R821 [3 H]-ICI-118,551 ...... Radiolabelled form of (0821)

1102 Procaterol...... Potentb2 agonist 0634 Salbutamol ...... bbb agonist (21 > )

b3-Adrenoceptor Selective Compounds

0948 BRL 37344 ...... b3 agonist 1134 CGP 12177 ...... bbb312 partial agonist. / antagonist 0929 ICI 215,001...... b3 agonist 0930 ZD 7114...... b3 agonist 0994 ...... b3 partial agonist. Also 5-HT 1A/1B antagonist 1060 (S)-(-)-Pindolol...... More active enantiomer

Generalb -Adrenoceptor Compounds

0435 ...... b agonist 0848 N-Desisopropylpropranolol...... metabolite

0515 Dobutamine...... bb12 and agonist. Also a 1 agonist 0832 ICI-89406 ...... b antagonist 0850 1-Naphthoxyacetic acid...... Propranolol metabolite 0849 1-Naphthoxylactic acid...... Propranolol metabolite 0829 Pronethanol...... b antagonist 0624 Propranolol...... b antagonist 0835 R-(+)-Propranolol ...... Less active enantiomer 0834 S-(-)-Propranolol ...... More active enantiomer 0851 Propranolol glycol...... Propranolol metabolite 0952 ...... b antagonist

Adrenergic Uptake Inhibitors

0935 ...... Noradrenaline re-uptake inhibitor 1025 Nisoxetine ...... Noradrenaline re-uptake inhibitor

Adrenoceptor Pharmacology, Tocris Reviews No. 8, November 1998, reprinted February 2000

Published and distributed by Tocris Cookson

Editor: Samantha Manley, Ph.D. Managing Editor: Duncan Crawford, Ph.D. Design and Production: Jane Champness; Lacia Ashman, MA

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