H

approach for numerous diseases. The new ligands should improve our knowledge of the physiological and pathophysiological interactions of different neurotransmitters and show new possibilities for the treatment of different diseases.

FURTHER READING

Buschauer, A., Schunack, W., Arrang, J.-M., Garbarg, M., Schwartz, J.-C. and Young, J.M. (1989) Histamine Receptors. In Receptor Pharmacology and Function, edited by M.Williams, R.M.Glennon and P.B.M.W.M.Timmermans, pp. 293-347. New York and Basel: Marcel Dekker, Inc.

Cooper, D.G., Young, R.C., Durant, G.J. and Ganellin, C.R. (1990) Histamine Receptors. In Comprehensive Medicinal Chemistry: The Rational Design, Mechanistic Study & Therapeutic Application of Chemical Compounds, edited by C.Hansch, pp. 323-421. Oxford and New York: Pergamon Press.

Hill, S.J. (1990) Distribution, Properties and Functional Characteristics of Three Classes of Histamine Receptor. Pharmacological Reviews 42, 45-83.

Krause, M., Rouleau, A., Stark, H., Luger, P., Garbarg, M., Schwartz, J.-C. and Schunack, W. (1995) Synthesis, X-ray Crystallography, and Pharmacokinetics of Novel Azomethine Prodrugs of (R)-a-Methylhistamine: Highly Potent and Selective Histamine H3-Receptor Agonists. Journal of Medicinal Chemistry 38, 4070-4079.

Leurs, R. and Timmerman, H. (1992) The Histamine H3-Receptor: A Target for Developing New Drugs. Progress in Drug Research 39, 127-165.

Lipp, R., Stark, H. and Schunack, W. (1992) Pharmacochemistry of H3-Receptors. In The Histamine Receptor, Ser. Receptor Biochemistry and Methodology, edited by J.-C. Schwartz and H.L.Haas, Vol. 16, pp. 57-72. New York and Basel: Wiley-Liss, Inc.

Schwartz, J.-C., Arrang, J.-M., Garbarg, M., Pollard, H. and Ruat, M. (1991) Histaminergic Transmission in the Mammalian Brain. Physiological Reviews 71, 1-51.

Zingel, V., Leschke, C. and Schunack, W. (1995) Developments in Histamine H1-Receptors Agonists. In Progress in Drug Research 44, 49-85.

10.4 DOPAMINE RECEPTORS Philip G.Strange

10.4.1 Introduction

Dopamine receptors have been very important targets for drug design by medicinal chemists partly because of the involvement of dopamine systems in important physiological functions and partly because dopamine receptors are important targets for drug action. In the brain dopamine systems are involved in the control of movement and certain aspects of behaviour, in the pituitary dopamine is important in the control of the secretion of prolactin and melanocyte stimulating hormone (a-MSH), in the cardiovascular system dopamine is important in the control of blood pressure and heart rate and in the eye dopamine is important for the control of certain aspects of visual function. In these systems the actions of dopamine are mediated by binding to receptors and blockade or activation of these receptors can offer therapy for certain disorders. For example, dopamine antagonists have been shown to be important in the treatment of schizophrenia, whereas dopamine agonists have been shown to be of use in the treatment of the brain disorder Parkinson's disease, in the therapy of excessive prolactin secretion and certain prolactin secreting tumours and in the therapy of cardiovascular disorders. For these reasons a very wide range of compounds has been synthesised that bind to receptors for the neurotransmitter dopamine. The development of the concept of multiple dopamine receptors has added further impetus to this drug discovery programme. Based on studies of the actions of dopamine using pharmacological and biochemical techniques it became apparent in the late 1970's that the concept of a single receptor for dopamine was insufficient to explain the information emerging and it was suggested that there were two receptors for dopamine that were termed D1 and D2. These had different pharmacological and biochemical properties some of which are summarised in Table 10.2. The concept of two dopamine receptors survived until the techniques of molecular biology were applied to the dopamine receptors. This showed that there were at least five dopamine receptor subtypes (D1-D5) which have different structural and functional properties and different localisations in tissues. Some of their properties are summarised in Table 10.3. This rather complicated picture can be simplified by the realisation that on the basis of structural and functional properties these five receptor subtypes can be grouped into two subfamilies: D1/D5 which have properties similar to those of the pharmacologically defined D1 receptor and D2/D3/D4 which have properties similar to those of the pharmacologically defined D2 receptor. The two subfamilies are therefore now termed the D1-like and D2-like subfamilies. In the subsequent discussion when a receptor is referred to as D1 this will imply that this is the receptor subtype defined by gene cloning whereas when the receptor has only been defined by pharmacological or biochemical analyses the nomenclature D1-like/D2-like will be used.

This emerging understanding of the multiple subtypes of dopamine receptors has importance for the way the activities of potential new dopamine receptor directed drugs are assayed. In early studies of these compounds animal behavioural tests were used e.g. the induction of stereotyped behaviour or the induction of turning in rodents; these tests detect dopamine receptor activity but do not distinguish compounds with selectivity for different receptor subtypes. The definition of D1-like and D2-like receptors from

Table 10.2 Dopamine receptor subtypes defined on the basis of biochemical and pharmacological studies.

Table 10.2 Dopamine receptor subtypes defined on the basis of biochemical and pharmacological studies.

Di (Di-like)

D2 (D2-like)

selective agonists

SKF 38393 (10.97)

quinpirole (10.96)

selective antagonists

SCH 23390*

sulphide*

biochemical response

cAMPf

cAMPj, K+ channel!,

Ca2+ channel^

The data in the Table are based upon the suggestion of Kebabian and Calne (1979) but have been expanded to include more recent information (Vallar and Meldolesi 1989). The original classification was into D1 and D2 receptor subtypes but, as discussed in the text, with

The data in the Table are based upon the suggestion of Kebabian and Calne (1979) but have been expanded to include more recent information (Vallar and Meldolesi 1989). The original classification was into D1 and D2 receptor subtypes but, as discussed in the text, with the advent of the isoforms defined by molecular biology (Table 10.3) these should be termed D1-like and D2-like receptors. *Formula in Table 10.4.

biochemical and pharmacological studies enabled compounds to be assayed for their interaction at the two subclasses using activity based assays e.g. the stimulation of adenylate cyclase for the D1-like receptors or using ligand binding assays. Most recently the availability of cloned genes for the five receptor subtypes has offered the prospect of the assay of selective substances for their activities against each subtype expressed in a suitable cell host using ligand binding assays or activity based assays.

The use of these different assay systems poses certain problems in the definition of the selectivity of compounds directed at the different receptors. This is particularly acute for the agonists where there are two qualities of an agonist that are potentially of interest; its affinity for the receptor and its ability to stimulate a response. In defining selectivity between receptors in activity based assays these two quantities are not always defined or separated and this can lead to confusion. Even in ligand binding assays there is potential confusion in extracting the relevant parameters for defining selectivity. Therefore in the discussion below "activity" will be referred to for agonists which is a broad definition of selectivity based on the tests used in the particular publication cited and should be taken only as a guide to actual selectivity. For antagonists there are fewer problems of this nature although the emerging phenomenon of "inverse agonism" may complicate matters.

10.4.2 Dopamine agonists

It was in the late 1950's that an independent role for dopamine as a neurotransmitter was postulated and this led to the development of models for the assessment of dopamine agonism mostly based on animal behavioural tests. From these tests it became clear that a number of naturally occurring or semisynthetic substances possessed dopamine agonist activity. Notable among these were the aporphine alkaloids e.g. apomorphine (10.79) and the ergot alkaloids e.g. ergotamine (10.80). At the same time synthetic programmes were initiated to obtain dopamine agonists with greater potency or activity and some of the important chemical classes of agonists will be considered below.

10.4.2.1 Aminotetralins and related compounds

A major synthetic effort has been devoted to compounds related to dopamine but where the dopamine molecule is "locked" in to a rigid structure. The best known examples of these are the aminotetralins. These have been synthesised in a variety of analogues with different hydroxyl substitution patterns on the aromatic ring. The 5,6-and 6,7-dihydroxy

aminotetralins (ADTN's) (10.81, 10.82) may be considered to be equivalent to the dopamine molecule, frozen into one or other of its two principal conformations (termed a and p conformations, 10.83, 10.84). The possibility of using these compounds to determine the active conformation of dopamine attracted much interest but it has not proven possible to draw any firm conclusion from the results of the studies.

The aminotetralins have activities at both the D1-like and D2-like subfamilies of dopamine receptors and it has been possible to draw some broad conclusions about the structure activity relationships involved. Compounds with two hydroxyl groups show the highest activity and the 5,6- and 6,7-congeners both have high activity. Substantial activity is retained in the monohydroxy compounds, for example the 5-hydroxy aminotetralins (eg. 10.85). The monohydroxy equivalents of dopamine (tyramines) also have some activity as dopamine agonists supporting this idea. Compounds lacking hydroxyl groups eg Ai,Ai-dipropyl-2-aminotetralin and phenylethylamine also exhibit weak agonist activity so these hydroxyl groups are not essential for agonist action. The amino group of the aminotetralins has been derivatised in a number of cases and this has shown that the addition of two alkyl groups enhances activity both at D1-like and D2-like receptors (eg.

OH OH

(10.85) (10.8i)

10.86). Activity increases with increasing alkyl chain length up to the di N-propyl derivatives which have the highest activities and the di A-butyl compounds which have less activity. It seems that there may be some additional site on the receptor with steric constraints which is occupied by these alkyl groups and which enhances agonist activity.

A series of 5-hydroxy aminotetralins has been synthesised where the A-n-propyl, A-phenylethyl and A-n-propyl, A-thenylethyl congeners are extremely potent agonists with substantial D2-like selectivity (10.87, 10.88). This suggests that particular groups larger than n-propyl can enhance potency further when attached to the aminotetralin structure. Generally the aminotetralins do not show great selectivity among the different D2-like receptors but 7-hydroxy-A,A' di n-propyl aminotetralin (10.89) has some selectivity for the D3 receptor mostly based on data from ligand binding assays.

10.4.2.2 Aporphine alkaloids

The aporphine alkaloids contain the dopamine structure in a rigid conformation. R(-)-apomorphine (10.79) has been shown to have D1-like and D2-like agonist activity although it tends to be a partial agonist at the D1-like receptors. The replacement of the A-methyl group with an A-propyl group in R(-)-A-propyl norapomorphine (10.90) increases the affinity for the D2-like receptors relative to the D1-like receptors.

10.4.2.3 Ergot alkaloids

A number of ergot alkaloids with dopamine agonist activity have been isolated from the crude mixture of natural products known as ergot. Typical examples of these are

{10.91); tt-ergocript! ne (10.92); bromocriptine

ergotamine (10.80) and a-ergocriptine (10.91) which contain the D-lysergic acid structure linked by an amide bond to a cyclic peptide moiety and these have come to be called "ergopeptines". Modification of these natural products by chemical synthesis has provided substances with better selectivity for dopamine receptors and notable here is bromocriptine (10.92) which has potent D2-like receptor activity but Drlike receptor antagonistic properties. It is used in the treatment of Parkinson's disease and excessive prolactin secretion.

A large number of semisynthetic "ergolines" exist where the structure is based on the lysergic acid structure and the peptide side chain of the ergopeptines has been eliminated. These have been shown to possess potent agonist activity at the D2-like receptors eg. lergotrile (10.93), pergolide (10.94), lisuride (10.95). Some of these compounds also possess significant agonist activity at the Drlike receptors eg pergolide, whereas others possess little or no agonist activity and in fact may be D1 partial agonists or antagonists depending on the test system eg lisuride (10.95).

Much synthetic work has ensued in order to identify the part of the ergoline that is responsible for the dopamine activity. Among the compounds synthesised are a group of partial ergolines including quinpirole (10.96) which is a very selective D2-like agonist.

10.4.2.4 Benzazepines

The benzazepine nucleus has been used to provide another series of molecules some of which are potent and selective D1-like agonists eg SKF 38393 (10.97), fenoldopam

(10.98). Other analogues exhibit activity at both the D1-like and D2-like receptors. Benzazepines also provide selective D1-like antagonists (see below).

10.4.2.5 Miscellaneous structures

The naphthoxazine PHNO (10.99) has been synthesised and is one of the most potent D2-like receptor agonists available with little ability to bind to or activate D1-like receptors. A^-n-Propyl-3-(hydroxyphenyl) piperidine (3-PPP) (10.100) is an example of a compound cl

(10.99); PHNO (10.100); 3-PPP

where the 3 (^-stereoisomer has D2-like receptor agonist activity whereas the 3 (S)-isomer has variable intrinsic activity depending on the receptor preparation. This can be seen as a preferential ability to act as an agonist at presynaptic autoreceptors but to behave as an antagonist at postsynaptic receptors. The compounds have little D1-like receptor activity.

10.4.2.6 Selective agonists

Compounds exist, as indicated above, that have the ability to act selectively as agonists on D1-like receptors eg SKF 38393 (10.97) or D2-like receptors eg quinpirole (10.96), PHNO 10.99). These compounds do not, however, show clear selectivity for the different isoforms comprising the two subfamilies with the exception of 7-OH DPAT (10.89) as mentioned earlier. In Table 10.3 some data are given for agonists from ligand binding studies illustrating this point. A second area where selectivity has been claimed for dopamine agonists is at autoreceptors. These are the receptors on dopamine nerve terminals or cell bodies that mediate inhibition of neurotransmitter synthesis, release or cell firing. It was found that although these receptors exhibited a pharmacological profile consistent with a D2-like receptor the autoreceptors were more sensitive to agonists compared to postsynaptic receptors. This would be consistent with autoreceptors being D2-like receptors but with a larger amplification (spare receptor ratio). This can at

Table 10.3 Dopamine receptor subtypes defined on the basis of molecular biological studies.

Di-like

D2-like

receptor isoform

Di

D5

D2

D3

D4

amino acids in human

446

477

414/443

400

419

receptor

pharmacological

properties

agonist binding (Ki nM)

(-)-apomorphine (10.79)

0.7

0.7

32

4

dopamine

0.9

0.9

7

4

30

quinpirole (10.96)

1900

4.8

24

30

7-OH DPAT (10.89)

5000

10

1

650

SKF 38393 (10.97)

1

0.5

150

5000

1000

antagonist binding (Ki

nM)

haloperidol*

80

100

1.2

7

2.3

chlorpromazine*

90

130

3

4

35

clozapine*

170

330

230

170

21

raclopride

18000

1.8

3.5

2400

remoxipride

240000

300

1600

2800

(-)-sulpiride*

45000

77000

15

13

1000

SCH 23390*

0.2

0.3

1100

800

3000

The different dopamine receptor isoforms can be distinguished structurally on the basis of the sizes of the predicted third intracellular loops and C-terminal tails (Civelli etal. 1993; Strange 1991). The Di-like receptors both have short third intracellular loops and long C-terminal tails whereas the D2-like receptors each have long third intracellular loops and short C-terminal tails. The D1-like and D2-like subgroups can also be distinguished on the basis of amino acid homologies. The data for Ki values shown in the Table are derived from Seeman and Van Tol (1994) and Hacksell etal. (1995) using ligand binding. There is some variability in the values derived from different studies and this is a particular problem for agonists where the complexities of agonist binding studies need to be considered. The selectivity of clozapine for D4 over D2 receptors (Seeman and Van Tol 1994) has not been found in all subsequent studies (Strange 1991; Hacksell etal. 1995). *Formula in Table 10.4.

least in part explain the apparent autoreceptor selectivity of 3^-3-PPP (10.100). If this compound is a partial agonist at the D2-like receptors then at receptors with a large amplification clear agonist activity will be seen but at receptors with a lower amplification factor antagonist activity may be exhibited. More recently compounds have also been synthesised with apparent auto receptor antagonist selectivity (see below).

10.4.3 Dopamine antagonists

In the early 1950's the phenothiazine, chlorpromazine, (Table 10.4) was discovered to have the ability to induce in humans a state of indifference without loss of consciousness and it began to be used as an anti psychotic drug. In the late 1950's the butyrophenone series of drugs was discovered e.g. haloperidol (Table 10.4) and these were shown to have anti psychotic activity. It was eventually found that a prominent action of these drugs was to inhibit various actions of dopamine and it became clear that one of their principal activities was as dopamine antagonists. The phenothiazines and butyrophenones

Table 10.4a The major classes of dopamine antagonists.*

Table 10.4a The major classes of dopamine antagonists.*

are D2-like antagonists and have varying abilities as D1-like antagonists. They also show varying abilities to act as serotonergic, muscarinic, histaminergic and adrenergic antagonists. Extensive synthetic programmes have been performed with the aim of developing more selective drugs with different structures and in Table 10.4 some of the key structural classes of dopamine antagonist are shown together with an indication

Table 10.4b The major classes of dopamine antagonists.

of their selectivity. Of note here are the benzazepines which are selective Di-like antagonists and the substituted benzamides which are selective D2-like antagonists.

While some of the compounds shown in Table 10.4 may show some selectivity between D1-like and D2-like receptors they do not in general have any marked abilities to

(10.101); (+VUH 212 (10.102); (+J-AJ 76

discriminate the individual members of the two subfamilies. Table 10.3 gives some data from ligand binding studies on the dissociation constants for some antagonists at the different receptor subtypes defined by gene cloning. It can be seen that there are some drugs such as raclopride that show low affinity for some receptor isoforms but there is at present no substance available that has a clear selectivity for a single receptor isoform. It was claimed that clozapine had a clear selectivity for the D4 receptor subtype but subsequent work has not reported the same selectivity.

Behavioural evidence for preferential actions of the compounds (+)-UH 232 (10.101) and (+)-AJ 76 (10.102) as antagonists at dopamine auto receptors has been presented but the relation of these findings to the different dopamine receptor isoforms is unclear. These compounds do show some selectivity for binding to the D3 dopamine receptor but the selectivity is not great. Extensive new synthetic programmes are currently in progress to develop compounds with clear selectivity for the different dopamine receptor isoforms and some selective agents are emerging (see, for example, Patel et al, 1996).

FURTHER READING

Beaulieu, M., Itoh, Y., Tepper, P., Horn, A.S. and Kebabian, J.W. (1984) N,N-disubstituted 2-aminotetralins are potent D2 dopamine receptor agonists. European Journal of Pharmacology 105, 15-21.

Cannon, J.G. (1983) Structure activity relationships of dopamine agonists. Annual Reviews of Pharmacology and Toxicology 23, 103-130.

Cavero, I., Massingham, R. and Lefevre-Borg (1982) Peripheral dopamine receptors, potential targets for a new class of antihypertensive agents. Life Sciences 31, 939948; 1059-1069.

Civelli, O., Bunzow, J.R. and Grandy, D.K. (1993) Molecular diversity of the dopamine receptors. Annual Reviews of Pharmacology and Toxicology 32, 281— 307.

Hacksell, U., Jackson, D.M. and Mohell, N. (1995) Does the dopamine receptor subtype selectivity of antipsychotic agents provide useful leads for the development of novel therapeutic agents? Pharmacology Toxicology 76, 320-324.

Hauth, H. (1979) Chemical aspects of ergot derivatives with central dopaminergic activity. In Dopaminergic Ergot Derivatives and Motor Function, edited by K.Fuxe and D.B.Calne, pp. 23-31, Oxford: Pergamon Press.

Hogberg, T. (1991) Novel substituted salicylamides and benzamides as selective D2 receptor antagonists. Drugs of the Future 16, 333-357.

Johansson, A.M., Arvidsson, L.E., Hacksell, U., Nilsson, J.L.G., Svensson, K. and Hjorth, S. et al. (1985) Novel dopamine receptor agonists and antagonists with preferential action on autoreceptors. Journal of Medicinal Chemistry 28, 10491053.

Kebabian, J.W. and Calne, D.B. (1979) Multiple receptors for dopamine. Aature (Lond.) 277, 93-96.

Leff, P. (1995) Inverse agonism: theory and practice. Trends in Pharmacological Sciences 16, 256.

Leysen, J.E. and Niemegeers, C.J.E. (1985) Neuroleptics. Handbook of Aeurochemistry 9, 331-361.

Martin, G.E., Williams, M., Pettibone, D.J., Yarborough, G.G., Clineschmidt, B.V. and Jones, J.H. (1984) Pharmacolgic profile of a novel potent direct-acting dopamine agonist, (+)-PHNO. Journal of Pharmacology and Experimental Therapeutics 230, 569-576.

Patel, S., Marwood, R., Emms, F., Marsten, D., Leeson, P.D., Curtis, N.R., Kulagowski, J. and Freedman, S.B. (1996) Identification and pharmacological characterisation of [125I] L 750,667 a novel radioligand for the D4 dopamine receptor. Mol. Pharmacol. 50, 1658-1664.

Seeman, P. (1980) Brain dopamine receptors. Pharmacological Reviews 32, 229-313.

Seeman, P. (1987) Dopamine receptors in brain and periphery. Aeurochemistry International 10, 1-25.

Seeman, P. and Van Tol, H.H.M. (1994) Dopamine receptor pharmacology. Trends in Pharmacological Sciences 15, 264-270.

Seeman, P., Watanabe, M., Grigoriadis, D., Tedesco, J.L., George, S.R., Svensson, U. et al. (1985) Dopamine D2 receptor binding sites for agonists. Molecular Pharmacology 28, 391-399.

Seiler, M.P. and Markstein, R. (1982) Further characterisation of structural requirements for agonists at the striatal dopamine D1 receptor. Molecular Pharmacology 22, 281-289.

Sibley, D.R. and Creese, I. (1983) Interaction of ergot alkaloids with anterior pituitary D2 dopamine receptors. Molecular Pharmacology 23, 585-593.

Sorensson, C., Waters, N., Svensson, K., Carlsson, A., Smith, M.W. and Piercey, M.F. et al. (1993) Substituted 3-phenyl piperidines: new centrally acting autoreceptor antagonists. Journal of Medicinal Chemistry 36, 3188-3196.

Strange, P.G. (1991) Interesting times for dopamine receptors. Trends in Neurosciences 14, 43-45.

Strange, P.G. (1992) Brain Biochemistry and Brain Disorders. Oxford: Oxford University Press.

Strange, P.G. (1994) Dopamine D4 receptors: curiouser and curiouser. Trends in Pharmacological Sciences 15, 317-319.

Vallar, L. and Meldolesi, J. (1989) Mechanisms of signal transduction at the dopamine D2 receptor. Trends in Pharmacological Sciences 10, 74-77.

Waddington, J.L. and O'Boyle, K.M. (1987) The D1 dopamine receptor and the search for its functional role: from neurochemistry to behaviour. Reviews in the Neurosciences 1, 157-184.

Wikstrom, H., Sanchez, D., Lindberg, P., Hacksell, U,., Arvidsson, L.E., Johansson, A.M. et al. (1984) Resolved 3-(3-hydroxyphenyl) N-n-propylpiperidine and its analogues: central dopamine receptor activity. Journal of Medicinal Chemistry 27, 1030-1036.

Wolf, M.E. and Roth, R.H. (1987) Dopamine autoreceptors. In Dopamine Receptors, edited by I.Creese and C.M.Fraser, pp. 45-96. New York: Alan R.Liss.

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