Indole Derived Structures

The indole derivative R0600175 (Fig. 3.5, compound 47) has been largely used as template for the development of 5-HT2C receptor agonists. This compound displayed high affinity for the 5-HT2C receptor, reasonably good selectivity over the 5-HT2A receptor (5-HT2C K. = 2.3 nmol/L; 5-HT2A K. = 14 nmol/L; 5-HT2B K. = 5.1 nmol/L), and considerable potency (EC50=18 nmol/L, 93% relative efficacy). Structural modifications of compound 47 have initially been focused on the optimization of the substitution pattern of the indole ring (Fig. 3.5, Structure I). In particular, the mono-substituted halogen derivatives in 4-, 5-, and 6-position of the indole ring showed higher 5-HT2C receptor affinity than the analogues bearing an electron-donating substituent (0CH3, CH3). The corresponding dihalogenated indoles (R=5-F, 6-Cl) showed the highest 5-HT2C receptor affinities within this series (8 < pK. < 9). In particular, derivative 48 (Fig. 3.5, Structure I, R=5,6-di-F) showed a better pharmacological profile than 47 (5-HT2C pK. = 9.0; 5-HT2A pK. = 7.0; pEC50 = 6.7, 100% relative efficacy). In general, the S-enantiomers displayed higher affinity and selectivity than their optical antipodes (Bös et al. 1997a).

Other 5-HT2C receptor agonists are 1,4-dihydroindeno[1,2-b]pyrroles with Structure II (Fig. 3.5). 0ptimization of the substitution pattern of the indole ring indicated that, differently from the indoles with Structure I (Fig. 3.5), methoxy-substituted 1,4-dihydroindeno[1,2-b]pyrroles showed higher affinities than the halo-genated counterparts. In this series, the 7-position was optimal for aromatic substitution. The introduction of a gem-dimethyl feature in the 1,4-dihydroindeno [1,2-b]pyrrole framework gave compound 49 (Fig. 3.5, Structure II, Rj = R6 = CH3, absolute configuration S). This derivative showed binding affinities for the human 5-HT2C and 5-HT2A receptors similar to R0600175 (47) (pK. values of 8.5 and 7.0, respectively), while displaying lower agonist potency in the 5-HT2B rat fundus assay (pD2 = 6.1 vs 7.9). Moreover, at the human 5-HT2B receptor, 49 was about 100-fold less potent than 47 (pEC50=7.26, relative efficacy of 91%) (Bös et al. 1997b).

Fig. 3.5 5-HT2C receptor agonists formally derived from R0600175 (47)

Several indoline derivatives were formally derived from 47 by reduction of the pyrrole ring (Fig. 3.5, Structure III). These compounds are potent partial agonists at the 5-HT2C receptor, since their affinities are broadly in the same range as 47, irrespective to the substitution pattern of the indole ring (3.2 nmol/L < K. < 26 nmol/L). The indoline 50 (Fig. 3.5, Structure III, R5 = F, R6 = Cl) showed similar selectivity (5-HT2A/5-HT2C K ratio = 12; 5-HT2A/5-HT2C K ratio = 2.2) as compared with the parent indole 47, but significantly lower binding affinity (Bentley et al. 2004).

A series of indazole derivatives have also been studied (Fig. 3.5, Structure IV). These compounds demonstrated moderate affinities (K > 37 nmol/L) and partial agonist properties at the 5-HT2C receptor but lacked binding and functional selectivity over 5-HT2A and 5-HT2B receptors (Adams et al. 2000).

Several 5-HT2C receptor agonists with a tricyclic core were designed based on 47. A first group of pyrroloquinoline derivatives originated from the fusion of the indole of 47 with a pyridine ring. An example is compound 51 (Fig. 3.5), which showed high 5-HT2C receptor affinity and an appreciable level of functional selectivity (5-HT2C K.=9 nmol/L; 5-HT2A K = 45 nmol/L; 5-HT2B K = 12 nmol/L; 5-HT2C EC50 = 12 nmol/L; 5-HT2A EC50=360 nmol/L). Other pyrroloquinolines possessed 5-HT2C affinities ranging between 22 and 156 nmol/L. These compounds acted as partial agonists and demonstrated relatively good functional selectivity (Adams et al. 2006).

In a second group, fusion of the indole of 47 with a cyclopentane ring gave the compounds with Structure V (Fig. 3.5). Although the pharmacological data were not exhaustive, it emerged that the S enantiomers displayed higher binding and functional selectivity over the 5-HT2A receptor. Variation of the indole ring substitution pattern resulted in moderate 5-HT2C receptor affinities (60 nmol/L < Ki < 474 nmol/L) and low binding selectivity over the 5-HT2A receptor. Conversely, some of these agonists were endowed with remarkable functional selectivity as in the case derivative 52 (Fig. 3.5, Structure V, R7=F; R8 = Cl; 5-HT2C EC50 = 36 nmol/L; 5-HT2A EC50 = 2,102 nmol/L) (Bentley et al. 2001).

The pyrazino[1,2a]indole framework (Fig. 3.6) has been extensively used for the design of 5-HT2C receptor agonists because it combines the structural features of mCPP (33) and of the indole derivative R0600175 (47).

The unsubstituted pyrazino[1,2a]indole 53 (Fig. 3.6) possessed low affinity for the 5-HT2C receptor (pK = 5.7), whereas the 10-methoxy substituted analog 54 (Fig. 3.6, Structure I, R=H) demonstrated much higher affinity (pK = 7.1). For this reason, a series of 10-methoxypyrazino[1,2-a]indoles bearing various substituents on the aromatic ring were evaluated (Fig. 3.6, Structure I). The affinity for the 5-HT2C receptor depended only upon the size of the substituent - neither the electronic properties nor the position on the aromatic ring were relevant. In fact, when R=H, 9-F, 9-CH3 low affinities were found (7.1 < pK < 7.6). By contrast, compounds with R=6-Br, 8-Br, 8-Cl, 9-CH(CH3)2 showed high 5-HT2C receptor affinities (8.0 < pKi < 8.3) and partial agonist properties (Bos et al. 1997b).

A group of compounds formally derived from 53 by saturation of pyrazino[1,2a] indole double bond (Fig. 3.6, Structure II) displayed acceptable agonistic properties at 5-HT2C receptors (13 nmol/L < EC50 < 162 nmol/L). Of the two enantiomers of 55 (Structure II, R=7-Cl) the R- was more potent than the S- (EC50 = 3 and 161 nmol/L, respectively).

The introduction of a CH3 group in 4-position of the Structure II (Fig. 3.6) generated an additional chiral centre. The new compounds have two stereogenic centers and a maximum of four enantiomers. The role of stereochemistry on 5-HT2C activity has been studied in the case of the four stereoisomers 56-59 (Table 3.4). Compound 56 (stereochemistry 4R,10aR) acted as full agonist with the highest affinity for all 5-HT2 receptors. The corresponding enantiomer 57 was about 100-fold less potent and acted as partial agonist. Compound 58 (stereochemistry

Fig. 3.6 5-HT2C receptor agonists with pyrazino[1,2a]indole framework

4S,10aR) and its enantiomer 59 were essentially full agonists and showed appreciable affinities for the 5-HT2C receptor with some selectivities against 5-HT2B receptors (7-16-fold). Based on these data, 56 was modified further (compounds 60-65, Table 3.4). Small lipophilic substituents at the 7 or 6 position (Cl, CN, CF3, and CH3) led to high affinity for the 5-HT2C receptor, whereas polar substituents (NHAc, CH2OH) led to a loss in affinity. Introduction of a 6-CH3 substituent in compounds 56 and 60 led to 66 and 67, respectively (Table 3.4). Derivative 67 showed remarkable subnanomolar agonist property and 66 was also selective over 5-HT2A and 5-HT2B receptors (> 10-fold) (Bentley et al. 2002; Rover et al. 2005).

Homologation of the nitrogen containing ring of pyrazino[1,2a]indole 53 gave rise to a series of azepino[1,7-a]indoles with Structure III (Fig. 3.6). Introduction of various alkyl groups on the basic nitrogen or of a range of substituents in 11-position gave compounds with modest 5-HT2C receptor affinity. The most active compound of the series was 68 (Fig. 3.6, Structure III, R1 = R2 = H) with K. values of 4.8 and 18 nmol/L at 5-HT2C and 5-HT2A receptors, respectively (Ennis et al. 2003).

3.3.3 Arylpiperazine Isosters

As pointed out above, arylpiperazines are poorly selective for 5-HT2C receptors. The search for basic moieties alternative to arylpiperazine and specifically acting at the 5-HT2C receptor has been pursued by researchers at Athersys Inc

Table 3.4 Binding affinities and relative efficacies of 5-HT receptor agonistsa

K, nmol/L

Compound

Stereochemistry

5-HT2C

5-HT2A

5-HT2B

Relative efficacy 5-HT2C (%)

56

7-Cl

4R,10aR

2.2

1.9

15

97

57

7-Cl

4S,10aS

180

430

2,600

62

58

7-Cl

4S,10aR

13

55

210

94

59

7-Cl

4R,10aS

22

61

160

87

60

7-CH3

4R,10aR

1.3

22

21

100

61

7-CF3

4R,10aR

1.4

7.5

11

94

62

7-CN

4R,10aR

3.8

110

90

77

63

7-NHAc

4R,10aR

680

1,100

960

24

64

7-CH2OH

4R,10aR

34

290

250

97

65

6-CH23

4R,10aR

2.6

43

59

100

66

6-CH3, 7-Cl

4R,10aR

0.3

2.6

3.2

98

67

6,7-di-CH3

4R,10aR

1.7

34

13

96

^Receptor binding assays were performed by using CHO cell line expressing recombinant human 5-HT2C, 5-HT2A and 5-HT2B receptors. Determination of affinities were made using [3H]-5-HT for 5-HT2C and 5-HT2B receptors, and [125I]-DOI for 5-HT2A receptors. The functional activity was determined in CHO cells using a Fluorometric Imaging Plate Reader. The maximum fluorescent signal was measured with the response produced by 10 mmol/L 5-HT

^Receptor binding assays were performed by using CHO cell line expressing recombinant human 5-HT2C, 5-HT2A and 5-HT2B receptors. Determination of affinities were made using [3H]-5-HT for 5-HT2C and 5-HT2B receptors, and [125I]-DOI for 5-HT2A receptors. The functional activity was determined in CHO cells using a Fluorometric Imaging Plate Reader. The maximum fluorescent signal was measured with the response produced by 10 mmol/L 5-HT

(Fig. 3.7). Initially, compound 69 was identified (EC50 = 0.1 mmol/L), then the homopiperazine ring was bioisosterically replaced with the 2,7-diazabicy-clo[3.3.0]octane system (compound 70, EC50 = 180 nmol/L). Of the possible enantiomers of 70, the best was the S,S isomer (EC50 = 23 nmol/L). The replacement of the pyrimidine ring with a phenyl gave the compound 71 that showed acceptable activity (EC50 = 103 nmol/L) but poor selectivity. Next, removal of the nonbasic nitrogen afforded the moderately potent agonist 72 (5-HT2C: EC50 = 420 nmol/L; 5-HT2A: EC50 = 1,080 nmol/L; 5-HT2B: EC50 = 187 nmol/L2 (Huck et al. 2006a). However, 72 presented unsuitable pharmacokinetic properties. In the search of better drug-like properties, the novel single-nitrogen motif was incorporated into a new tricyclic scaffold (Fig. 3.7, Structure I). The presence of CH3 in 8-position (absolute configuration S) was beneficial for the specificity and two substituents on the aromatic ring (especially a halogen atom) enhanced activity. The most active compounds of this series (73-80) are listed in Table 3.5 (Huck et al. 2006b).

Another tricyclic system that retained the three-dimensional orientation of the basic amine in relation to the core phenyl ring in a similar manner as the compounds

Fig. 3.7 Bicyclic basic moieties alternative to 1-arylpiperazine

73-80 is depicted in Fig. 3.7 (Structure II). Various substituents in 7 position of the racemic pyrazinoisoindolone system were evaluated. CF3, 0CF3, and SCH3 substituents were preferred due to their reduced electron-donating properties rather than the hydrophobic ones. From the optical resolution of the racemic mixture of the derivative 81 (Fig. 3.7, Structure II, R = CF3), it emerged that the R-enantiomer was significantly more potent than the S-enantiomer at 5-HT2C receptor (EC50 = 7 and 1,840 nmol/L, respectively). Therefore, for the subsequent modifications, only the R-enantiomers were considered. Insertion of an alkyl on various positions of the fused piperazine ring of R-81 was detrimental for activity, especially when the steric hindrance was introduced near the basic nitrogen

Table 3.5 Binding affinities of 5-HT receptor agonistsa

Compound R5

Selectivity vs (fold)

Compound R5

Selectivity vs (fold)

5-HT2C

5-HT2A

5-HT2B

73

OCH3

Cl

H

14

73

235

74

och3

Br

H

27

12

81

75

OC2H5

Cl

H

231

9

31

76

OH

Cl

H

27

27

63

77

CH3

Cl

H

155

8

32

78

Cl 3

CH3

H

134

11

14

79

Cl

Cl 3

H

155

8

32

80

H

Cl

Cl

5

50

73

Experimental details were not presented in the original publication

Experimental details were not presented in the original publication

(Fig. 3.7, Structure III). Investigation of the substitution pattern of the aryl ring (Fig. 3.7, Structure IV) indicated that 7,9-disubstituted derivatives presented the most interesting properties, because although their potency was not extremely high (49 nmol/L < EC50 < 86 nmol/L), they displayed >100-fold functional selectivity over 5-HT2A and 5-HT2B receptors. Conversely, 7,10-disubstituted derivatives were significantly less potent, whereas 7,8- and 8,9-disubstituted compounds displayed high potency but little or no selectivity. Particular attention has been devoted to the 7,9-disubstituted derivatives bearing CF3 in 7 position (Fig. 3.7, Structure V). The presence in 9 position of -Cl or polar functionalities (Ac, CH2OH) decreased activity, whereas 9-OCH3 and 9-OCH2CH3 gave acceptable functional potency at 5-HT2C (EC50 = 11 and 63 nmol/L, respectively). The 9-CH3-substituted derivative was a very potent 5-HT2C agonist (EC50 = 6 nmol/L) that was 27- and 47-fold functionally selective over 5-HT2A and 5-HT2B, respectively. Increasing the size of the C9 substituent resulted in a decrease in 5-HT2C potency; the propyl, butyl, and isopropyl derivatives no longer exhibited high 5-HT2C functional efficacy but showed high excellent functional selectivity. The 9-ethyl derivative possessed good 5-HT2C functional potency (EC50 = 16 nmol/L) and was >300-fold functionally selective over 5-HT2B and 73-fold selective over 5-HT2A (Wacker et al. 2007).

3.3.4 Benzazepine Derivatives

The arylethylamine motif, which is present in a number of nonselective 5-HT2C agonists, including 5-HT and norfenfluramine (82, Fig. 3.8) has been the starting point for the design of a series of 3-benzazepine derivatives

Fig. 3.8 Development of 5-HT2C receptor agonists with 3-benzazepine structure

(Fig. 3.8, Structure I). In this structure type, the arylethylamine motif is constrained into a bicyclic system, which would reduce the number of available conformations to such a degree that target selectivity could be altered. During the development of this series only the functional activity of the target compounds at the h5-HT2C (INI isoform), h5-HT2A, and h5-HT2B receptors was assessed by measuring the [3H]IP turnover. The unsubstituted 3-benzazepine (83) displayed low potency at the 5-HT2C receptor (pEC50 = 5.5), whereas the introduction of a methyl in 1-position (compound 84: Fig. 3.8, Structure I, X = H) resulted in an increase of potency at the 5-HT2C receptor (pEC50 = 6.5). The search for the optimal aromatic substitution pattern on 84 was accomplished. Monosubstitution at the 8-position (X = Cl, Br, CF3) or at the 7-position (X = Cl) gave good 5-HT2C potency (7.9 < pEC50 < 8.1), whereas the presence of OCH3 or F at 7 or 8 position led to a reduction in potency (5.9 < pEC50 < 6.7). 6- or 9-Cl substituted compounds also showed low potency (pEC50 = 6.1). Introduction of an additional substituent in 7 or 9 position of the 8-chloro-1-methylbenzazepine (compound 85, Table 3.6) resulted in potent compounds (8.1 < pEC50 < 8.4), regardless of the nature of the substituent (Cl, F, OCH3). The role of C1 stereochemistry was investigated for compounds 85-90. Biological data revealed some stereospecificity but not all the eutomers showed the same absolute configuration (Table 3.6). The most selective compounds were the benzazepines S-89 and S-90 that were at least 40- and 400-fold selective over 5-HT2A and 5-HT2B receptors, respectively (Smith et al. 2008).

3.4 Conclusions

Among the 14 receptor subtypes of serotonin, the 5-HT2C subtype has received much attention because of its possible involvement in clinically relevant disease conditions such as schizophrenia and obesity. The studies performed by researchers at GlaxoSmithKline have led to the identification of several potent and selective 5-HT2C receptor antagonists. The large body of data on antagonists has allowed a detailed description of a pharmacophore model for 5-HT receptor antagonists as

Table 3.6 Intrinsic activities of 5-HT receptor agonists with 3-benzazepine structurea

PEC,

Compound

X

5-HT2C

5-HT2A

5-HT2B

85 (racemic)

8-Cl

7.9

6.7

6.0

R-85 (lorcaserin)

8-Cl

8.1

6.8

6.1

S-85

8-Cl

7.8

6.6

5.9

R-86

8-CF3

8.1

6.9

6.3

S-86

8-CF3

8.0

7.0

6.1

R-87

7,8-di-Cl

8.4

8.0

7.4

S-87

7,8-di-Cl

8.1

7.0

6.6

R-88

8-Cl, 7-OCH3

8.1

6.7

6.4

S-88

8-Cl, 7-OCH3

8.2

7.5

7.4

R-89

8,9-di-Cl

6.5

5.6

<5

S-89

8,9-di-Cl

8.5

6.9

5.9

S-90

8-Cl, 9-F

8.4

6.0

<5

aThe functional activities were determined in HEK293 cells overexpressing human 5-HT2A 5-HT, or 5-HT receptor with the intracellular inositol triphosphate (IP3) accumulation assay well as the description of the topography of the antagonist binding site of the receptor. On the other hand, studies from different laboratories have led to the identification of functionally selective 5-HT2C receptor agonists. This was a difficult task because the 5-HT2C receptor structure is closely related to that of the 5-HT2A and 5-HT2B receptor subtypes. Although information is available to describe the structure-activity relationships of the agonist, no pharmacophore model has been proposed to date. In recent years two 5-HT2C agonists [lorcaserin (R-85) and ATHX-105] entered phase II clinical trials for treatment of obesity. The outcome of these studies will reveal the validity of the 5-HT2C receptor as a pharmacologically treatable target and will likely fuel the search for newer selective agents for 5-HT2C receptors.

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