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Aporphine Alkaloids as Ligands for Serotonin Receptors

Nirav Kapadia1,2* and Wayne Harding1,2

1Department of Chemistry, Hunter College, City University of New York, 695 Park Ave, New York, NY 10065, USA

2Chemistry Program, Graduate Center, City University of New York, 365 Fifth Ave, New York, NY 10035, USA

*Corresponding Author:
Nirav Kapadia
Department of Chemistry
Hunter College, City University of New York
695 Park Ave, New York, NY 10065
Tel: 212-772-5330
E-mail: nrkkap[email protected]

Received date: March 26, 2016; Accepted: April 12, 2016; Published: April 18, 2016

Citation: Kapadia N, Harding W (2016) Aporphine Alkaloids as Ligands for Serotonin Receptors. Med chem (Los Angeles) 6:241-249. doi:10.4172/2161-0444.1000353

Copyright: © 2016 Kapadia N, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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The aporphine alkaloids are known to have affinities as the dopaminergic, adrenergic and serotonergic receptor system. Hence the aporphine template can be considered as a privileged scaffold for the design of selective monopotent as well as multi-potent Central Nervous System (CNS) ligands. This review attempts to summarize the recent Structure Activity Relationship (SAR) studies of aporphine alkaloids specifically at the serotonin receptor system. Based on the obtained SAR information it can be concluded that aporphines have great potential to be developed as potent serotonergic ligands.


Aporphine; Central nervous system; Ligands; Alkaloids


Aporphine alkaloids are natural and synthetic alkaloids that possess a tetracyclic framework. Chemically they incorporate a tetrahydroisoquinoline substructure and belong to the isoquinoline class of alkaloids. More than 500 members of this class of alkaloids have been isolated. Aporphine alkaloids are widely distributed in Annonaceae, Lauraceae, Monimiaceae, Menispermaceae, Hernandiaceae and other plant families [1] (Figure 1).


Figure 1: Basic aporphine skeleton.

Both naturally occurring and synthetic aporphine alkaloids possess diverse range of pharmacological actions. Figure 1 shows the basic aporphine skeleton [2].

Pharmacological Effects of Aporphine Alkaloids

Aporphine alkaloids exhibit a plethora of effects within the Central Nervous System (CNS). There are a number of aporphine alkaloids reported as ligands at dopamine and serotonin receptors [1,3]. Ligands at the D1 and D2 dopamine receptor subtypes have a potential role in the treatment of Parkinson’s disease, schizophrenia, Attention Deficit Hyperactivity Disorder (ADHD), depression, and drug abuse [4-6]. In fact, (R) - Apomorphine (2) which is considered to be a prototype of aporphine alkaloids by many, has been approved for the treatment of advanced stages of Parkinson’s disorder [7]. Ligands at the 5-HT1A serotonin receptor subtype have been useful in the treatment of anxiety, schizophrenia and depression [8-11] (Figure 2).


Figure 2: (R) – Apomorphine.

Aporphines are also ligands at the 5-HT2A and 5-HT7 receptors. Selective 5-HT2A ligands have promising applications in the treatment of drug abuse and insomnia. Mixed dopamine/5-HT2A ligands have potential for the alleviation of symptoms of depression and schizophrenia [12,13]. Ligands at the 5-HT7 receptor have shown promising results for the treatment of sleep disorders, migraine and depression [14-16]. Moreover aporphines possessing affinity at the dopamine and serotonin receptors have potential use as PET (Positron Emission Tomography) and SPECT (Single Photon Emission Computed Tomography) radiotracers for brain imaging studies [17]. Aporphines are also reported as inhibitors of the enzyme Acetylcholinesterase and as antagonists of the α1-adrenergic receptor and thus have potential therapeutic role in the treatment of Alzheimer’s disease and hypertension respectively [18-21].

Thus the aporphine scaffold can be considered a privileged scaffold for the design of CNS ligands. A majority of the work in the early 1990s has focused on the design of aporphine alkaloids as ligands for the dopamine receptor system. In terms of the serotonin receptors, aporphines have mostly been studied as ligands at the 5-HT1A receptor. Some of this previous work has been nicely summarized in previously Published reviews [1,3].

Aporphine as 5-HT1A Ligands

The first aporphine alkaloid reported as a selective serotonin ligand was reported by Canon and co- workers in 1988 [22]. The (R) - (-) - 10-Methyl-11-hydroxyaporphine (R - 3) (Figure 3) was originally designed as a dopamine receptor ligand. Surprisingly R - 3 displayed serotonergic agonistic activity with a high degree of selectivity for the 5-HT1A receptor. Further studies revealed that the S isomer of 3 (S - 3) was an antagonist at the 5-HT1A receptor [23]. This trend of enantiomers having opposing pharmacological effects was found to be consistent with other aporphine enantiomers displaying opposing effects at the dopaminergic receptors (Figure 3).


Figure 3: Structure of R and S enantiomers of compound 3.

In order to probe the role of the C-10 methyl group compound 4 that lacked a C-10 methyl group was evaluated for dopaminergic and serotonergic activity. Both the enantiomers of compound 4 were found to possess dopaminergic activity but lacked any appreciable serotonin 5-HT1A activity [24]. This clearly indicated a significant role of the C-10 methyl group towards the enhanced 5-HT1A affinity of 3 (Figure 4).


Figure 4: Structure of R and S enantiomers of compound 4.

It was further shown that both the C-10 methyl and C-11 hydroxyl group in compound 3 are required for affinity at the 5-HT1A receptor. This was evident from the observed lower affinity of the mono methylated compound 5 [25]. Furthermore, the high affinity at the 5-HT1A receptor of compound 3 is unique and specific to an 11-hydroxy, 10-methyl substitution pattern. Having this substitution at other positions (such as in compounds 6 and 7) resulted in complete loss of affinity at the 5-HT1A receptor [26]. High affinity for the 5-HT1A receptor was also observed in the case of compound 8, which possesses a similar ortho hydroxyl/hydroxyl methyl substitution [27] (Figure 5).


Figure 5: Structure of R and S enantiomers of compounds 5, positional isomers 6 and 7 and compound 8.

Based on molecular docking studies, the C-11 hydroxyl group makes a hydrogen bond interaction with Ser198 and Ser193 residues of the 5-HT1A and D2 receptors respectively. The main difference however is the interaction of the C-10 methyl group wherein it interacts with a lipophilic pocket in the 5-HT1A receptor, which is not available in the case of the D2 receptor. The absence of a similar lipophilic pocket around the C-10 methyl group in the D2 receptor explained the high selectivity of 3 for the 5-HT1A receptor over the D2 receptor [28].

The existence of this lipophilic pocket was further tested by Hedberg and co-workers by the evaluation of a series of C-10 substituted aporphine compounds [29]. Substitution of bulky groups at the C-10 position (compound 9, 10, 11 and 12) resulted in dramatic loss of affinity for the 5-HT1A receptor whereas small alkyl group substituents (compound 13) were well tolerated, thus confirming the existence of the lipophilic “methyl” pocket, which is able to accommodate only small groups.

In contrast to the previously observed strict requirement of a C-11 hydroxyl/C-10 methyl substitution, a series of mono C-11 substituted aporphine compounds (14, 15 and 16) were found to have good affinity as well as selectivity for the 5-HT1A receptors [29]. Based on molecular modeling studies substituents at the C-11 position interacted in a manner that was different from the previously seen hydrogen bond interaction of the C-11 hydroxyl group with the 5-HT1A receptor. In the case of C-11 substituents, significant interactions were seen with a pocket lined by Ser168, Met172, Thr196. Ser199, Thr200, Phe362, Ala365 and Leu366. This indicated that the proposed methyl pocket was much larger, and suitable C-11 substituents could interact with it. This hypothesis of a larger lipophilic pocket was further confirmed by Zhang et al. by the synthesis and evaluation of compounds 17, 18 and 19 that lacked a C-11 hydroxyl group yet displayed high affinity at the 5-HT1A receptor [30].

Other reported SAR studies include the evaluation of C10 substituted long chain carbamate (20 and 21) or amide (22 and 23) aporphines [31]. These compounds displayed only moderate affinity at the 5-HT1A receptor as shown in Table 1. Similarly limited studies have been done at other positions of the aporphine scaffold with regards to the 5-HT1A affinity. Zhang and co-workers reported the evaluation of C-2 substituted aporphine compounds (24, 25 and 26) which did not show any appreciable affinity at the 5-HT1A receptor, although the number of compounds studies are too less to make a general conclusion [32] (Figure 6).


Figure 6: Structure of compounds 24, 25 and 26.

Compound R1 R2 R3 R4 Ki(nM) Ref.
          5-HT1A D1 D2  
R-3 OH Me H Me 0.45 382 1070 [22,29]
S-3 OH Me H Me 39 - - [23]
R-4 OH H H Me 296 236 41.90 [24,29]
S-4 OH H H Me - - - [24]
R-5 H Me H Me 1.20a - - [25]
S-5 H Me H Me 6.80a - - [25]
6 H OH Me Me - - - [26]
7 H Me OH Me - - - [26]
8 OH CH2OH H Me 2.4 1390 7000 [27]
9 OH Ph H Me 1090 9400 >1000 [29]
10 OMe 2-furyl H Me 995 14000 582 [29]
11 OH COMe H Me 1720 4620 2760 [29]
12 OMe CH=CH2 H Me 108 1440 1750 [29]
13 OH Et H H 9.20 782 2050 [29]
14 Ph H H Me 1.80 3630 233 [29]
15 2-OMe-Ph H H Me 26.90 >3000 1330 [29]
16 2-OH-Ph H H Me 28.50 3750 1570 [29]
17 OCH2CCH H H Pr 55 - - [30]
18 O-Allyl H H Me 12 - - [30]
19 OCH2CCH H H Me 14 - - [30]
20 NHCOOEt H H Pr 94 54.6b 44.3b [31]
21 NHCOOtBu H H Pr 96 70.2b 871 [31]
22 NH2 H H Pr 276 57.1b 352 [31]
23 NHCOPr H H Pr 380 16.1 13.5 [31]
27 OH Me H H 3.20 23800 >10000 [29]
28 OH Me H Pr 12.30 >2000 249 [29]

Table 1: Affinityvaluesof aporphinederivativesat the5-HT1Areceptor.

Although an N-methyl group is not absolutely required for 5-HT1A affinity as indicated by compounds 27 and 28, an increase in affinity and selectivity for the 5-HT1A receptor was observed when the size of the substituent was decreased to a methyl or a hydrogen group (Table 1).

Aporphines as 5-HT2A Ligands

Majority of the work of aporphine alkaloids as ligands at the 5-HT2A receptor has mainly focused on the natural alkaloid nantenine. Nantenine (29) was isolated from the fruit of Nandina domestica Thunberg [33]. Indra and co-workers in 2002 showed that nantenine inhibited 5-hydroxy-L-tryptophan (l-5-HTP) induced head-twitch response by blocking 5-HT2A receptors in mice [34]. Later the same group reported SAR studies showing nantenine as an antagonist at the 5-HT2A and α1 receptors [35,36]. Studies done by Fantegrossi revealed the ability of nantenine to block and reverse MDMA induced physiological effects such as hyperthermia, locomotor stimulation and head-twitch responses in mice. These anti-MDMA effects of nantenine were attributed to its antagonism at the 5-HT2A and α1 receptors [37] (Figure 7).


Figure 7: Structure of (±)-nantenine.

Research in our group has focused on the synthesis and evaluation of nantenine analogues as 5- HT2A antagonists. The first accomplished step in this direction was to synthesize racemic nantenine and screen it across available CNS receptors via the Psychoactive Drug Screening Program (PDSP) of the NIH. Results from this screening showed that nantenine is highly selective for the α1A receptor (Ki=2 nM) compared to other α1A subtypes. At the 5-HT2A receptor, nantenine was found to have moderate affinity (Ki=850 nM) [38]. In order to improve the potency and selectivity of nantenine analogues for the 5-HT2A receptor, a systematic SAR study was initiated. A brief discussion of our previous findings is described.

At the C1 position several linear and branched alkyl substitutions were evaluated [39,40]. Table 2 shows the binding affinity (Ke) values for a series of C1 substituted nantenine analogues. Progressive increase in the alkyl chain length at this position, resulted in increased affinity at the 5-HT2A receptor. More importantly the affinity of these compounds at the α1A receptor was completely abolished, thus suggesting that the C1 position could play a vital role in fine tuning the selectivity of nantenine. As seen in Table 2, the C1 ethyl analogue (30, Ke=890 nM) was found equipotent to nantenine. Substitution with propyl (31, Ke=297 nM) and butyl (32, Ke=274 nM) groups resulted in three times increase in potency. The n-hexyloxy analogue (34, Ke=71 nM) which was the most potent compound identified in this series, was 11 times more potent than nantenine at the 5-HT2A receptor. Compound 35 which can be considered as branched analogue of the n-butyl analogue also displayed significant improved affinity (35, Ke=68 nM). However an increase in the size of the ring (from 3 membered up to 6 membered) resulted in either compounds having weak agonist activity (36 and 37) or compounds having complete loss of affinity (38). Alternatively compound 39 which is an open chain analogue of the cyclopropyl analogue methyl analogue resulted in a 5 fold drop in affinity. Similarly homologation of 39 to compounds 40 and 41 produced compounds having reduced affinity for the 5-HT2A affinity.

Compound R1 Ke(nM)a Ref.
    5-HT2A α1A  
(±)-29 Me 850 36 [39]
30 Et 890 - [39]
31 n-Pr 297 - [39]
32 n-Bu 274 - [39]
33 n-Pen 171 - [39]
34 n-hex 71 >10000 [40]
35 CyclopropylMe 68 >10000 [40]
36 CyclobutylMe ND >10000 [40]
37 CyclopentylMe ND >10000 [40]
38 CyclohexylMe 1722 >10000 [40]
39 Isobut 367 >10000 [40]
40 Isopen ND >10000 [40]
41 2-EthylBu 806 >10000 [40]
42 allyl 70 >10000 [40]
43 CH2CN >10000 711 [41]
44 CH2CH=CHCH3(E) 723 1980 [41]
45 CH2CH=C(CH3)2(E) 2074 >10000 [41]
46 CH2C6H4-p-Br 9.2 >10000 [41]

Table 2: Binding affinity data of C-1 nantenine analogues.

Incorporation of an allyl group at the C1 position resulted in comparable activity to the cyclopropylmethyl analogue. This can be attributed to the electronic similarity between the allyl and the cyclopropylmethyl group. (42, Ke=70 nM). In a more recent study, we explored several other allylic groups at the C1 position [41]. Overall from this study it was concluded that branched allylic substituents (compounds 44 and 45) as well as other allylic isosteric replacements (compound 43) were not tolerated for affinity at the 5-HT2A receptor. Compound 46 that has a p - bromobenzyl unit attached at the C1 position was the most potent 5-HT2A ligand identified in this series. In fact compound 46 is the most potent 5-HT2A aporphinoid antagonist known till date (Table 2).

Molecular modeling studies were used to identify key interactions of the 5-HT2A receptor with the nantenine analogues [42]. Accordingly the protonated nitrogen atom and the oxygen atom in the methylenedioxy ring are involved in a hydrogen bond interaction with the Asp155 and Ser242 residues respectively. In addition, the alkyl side chain of the C1 alkyl analogues is buried in a hydrophobic pocket comprising of Phe234, Gly238, Leu228 and Ile341 side chains. This interaction seems to be critical for the observed enhanced affinity of the C1 alkyl analogues. Alternatively the moderate affinity of nantenine can be explained by the lack of this hydrophobic interaction.

At the C2 position the effect of small alkyl group substitution was studied [40]. Replacement with ethoxy (47, Ke=378 nM) and propyloxy groups (48, Ke=485 nM) resulted in a moderate (2 and 1.7 times respectively) increase in potency. However replacements with larger alkoxy groups were detrimental for 5-HT2A receptor affinity (49, Ke=943 nM; and 33, Ke>10,000 nM). These substitutions also led to a decrease in affinity at the α1A receptor and a similar trend (decreased affinity with increase size of the alkyl substitution) was observed. Compound 52 (Ke=154 nM) with a benzyloxy group at the C2 position was the most potent compound in this series. Overall a C2 group larger than propyl is not well tolerated for affinity at the 5-HT2A receptor. A substitution at the C2 position is not absolutely required for affinity at the 5-HT2A receptor as exemplified by compound 53 [43].

Replacement of the N-methyl group with other groups (compound 54 - 58) resulted in complete loss of affinity for the 5-HT2A receptor, but affinity at the α1A receptor was retained. This suggested that the N-Methyl group is important for affinity at the 5-HT2A receptor. This trend is in contrast to the effect of similar N-substituted aporphine alkaloids at the 5-HT1A and dopamine D1 and D2 receptors. Molecular docking studies indicate that the protonated nitrogen atom is involved in a hydrogen bond interaction with an Asp155 residue of the 5-HT2A receptor. The requirement of this salt bridge interaction was proven by evaluating the isochroman compounds 59 and 60 which were found to be completely inactive at the 5-HT2A receptor [43].

It is also worth mentioning that both the R and S enantiomers of nantenine displayed antagonist effects at the 5-HT2A receptor. This trend is in contrast to the effect of aporphine enantiomers at other receptor system including 5-HT1A and dopamine D1 and D2, where enantiomers display opposing pharmacological effects as previously described. Furthermore in an in vivo rat assay, both the R and S enantiomers of nantenine completely blocked the effects of MDMA at a dose of 0.3 mg/kg. This observation was found in concurrence by previous observations made by Indra et al. (Table 3).

Compound R1 R2 R3 Ke(nM) Ref.
        5-HT2A α1A  
47 Me Et Me 378 52 [40]
48 Me n-Pr Me 389 133 [40]
49 Me n-Bu Me 943 234 [40]
50 Me n-Pen Me >10000 449 [40]
51 Me CyclopropylMe Me 484 195 [40]
52 Me Bn Me 154 1917 [40]
53 Allyl H Me 47 744 [40]
54 Me Me N-Et >10000 26 [40]
55 Me Me N-nPr >10000 38 [40]
56 Me Me N-nBu >10000 210 [40]
57 Me Me N-nPen >10000 720 [40]
58 Me Me N-CyclopropylMe >10000 319 [40]
59 Me Me O >3000 >3000 [43]
60 Allyl Me O >3000 >3000 [43]
(R)-29 Me Me N-Me 946 70 [43]
(S)-29 Me Me N-Me 657 196 [43]
(±)-29 Me Me N-Me 850 36 [39]

Table 3: Binding affinity data of C-2 and N6 nantenineanalogues.

Substitutions at the C3 position included the evaluation of a series of C3 halogenated compounds 62-66 [44]. In general halogenation is very well tolerated at the C3 position and all the halogenated nantenine analogues displayed enhanced 5-HT2A affinity. Compounds 62-64 showed doubling of 5-HT2A antagonist potency (compared to their non-halogenated counterpart (61) irrespective of the halogen group present. Methylation of the C2 OH group resulted in further enhancement in the 5- HT2A potency as seen by the C3 chloro (65) and C3 bromo (66) compounds respectively. This trend in enhancement of affinity following C3 halogenation has been reported in other aporphine compounds at the dopamine D1 and D2 receptors as well as for the α1 adrenergic receptor subtypes (i.e., α1A, α1B, and α1D receptors) (32).

Modeling studies show the C3 halogenated compounds to have a completely different binding pose than the non-halogenated aporphines. In the case of the halogenated aporphines, the C3 halogen atom is oriented towards F339 and F340 residues, and it is this interaction that might be responsible for the higher affinity observed in this series of compounds. This lipophilic space can be further explored by suitable C3 hydrophobic substituents (Table 4).

Compound R1 X Ke(nM)
      5-HT2A α1A
61 OH H 282 255
62 OH Cl 130 1279
63 OH Br 126 68
64 OH I 133 60
65 OMe Cl 63 1273
66 OMe Br 48 >10000
(±)-29 OMe H 850 36

Table 4: Binding affinity data of C-3 nantenine analogues.

Aporphines as 5-HT2B Ligands

Recently we reported a fortuitous discovery wherein a series of aporphine alkaloids having a C4 phenyl group were found to have affinity for the 5-HT2B receptor [45]. These compounds were initially designed to increase the 5-HT2A receptor affinity of nantenine; however to our surprise displayed no appreciable affinity for the 5-HT2A receptor. This clearly indicated that a phenyl group at the C4 position of nantenine is detrimental for its 5-HT2A receptor affinity. This in turn might be due to the inability of the 5-HT2A binding cavity to accommodate the C4 phenyl group or due to a steric clash between a receptor side chain and the C4 phenyl group. Amongst this series, compound 67 had the highest affinity for the 5-HT2B receptor (Ki=96 nM). When nantenine (5-HT2B, Ki=534 nM) is compared to compound 67 it is apparent that the C4 phenyl substituent positively impacts 5-HT2B affinity and selectivity. Binding affinity of other analogues indicated a clear trend between the length of alkyl group at the C1 position and 5-HT2B receptor affinity. Thus with increasing C1 alkyl chain length, the 5-HT2B receptor affinity was found to decrease as evident from compound 67 to 71. A similar trend was also observed with respect to the size of the N6 alkyl substituent in compounds 67, 76 and 77. Thus the larger the N-alkyl group the lower is the 5-HT2B receptor affinity. Both the trends suggest that the binding pocket occupied by the C1 alkyl and N6 alkyl groups are small and do not accommodate larger substituents. The C1 cyclopropylmethyl analogue (72, Ki=299 nM) has similar affinity compared to the propyl analogue (69, Ki=307 nM), which indicates that some degree of branching is tolerated. The allyl analogue (73, Ki=416 nM) had reduced affinity compared to its saturated analogue (69, Ki=307 nM) suggesting that saturation in this part of the alkyl chain is not tolerated. A phenolic OH group is not well tolerated for 5-HT2B receptor affinity as indicated by 75 (Ki=715 nM) (Table 5).

Compound R1 R2 5-HT2A-Ke(nM)
67 Me Me 96
68 Et Me 209
69 n-Pr Me 307
70 n-butyl Me 601
71 hexyl Me 663
72 CyclopropylMe Me 299
73 allyl Me 416
74 p-bromobenzyl Me ND
75 H Me 715
76 Me Et 419
77 Me CyclopropylMe 1429
(±)-29 OMe Me 850

Table 5: Binding affinity data of C-4 phenyl nantenine analogues.

Compound 67 has excellent selectivity for the 5-HT2B receptor as it did not display any affinity across a broad range of other CNS receptors (α1A, α1B, α1D, β1, β2, β3, BZP rat brain site, CB2, D1, D2, D3, D4, D5, DAT, DOR, GABAA, H1, H2, H3, H4, KOR, M2, M3, M4, M5, MOR, NET, NMDA, SERT, sigma-1, sigma-2). 67 showed affinities for the following receptors other than 5-HT2B: 5- HT6 (627 nM), α2a (719 nM), α2B (3220 nM), α2C (433 nM) M1 (>10,000 nM) and PBR (2897 nM). In the 5-HT2B functional activity testing, 67 displayed antagonistic activity (IC50=1 μM). It is also of relevance that no 5-HT2B agonist activity was found. To the best of our knowledge compound 67 is the first reported aporphine alkaloid to have selective affinity for the 5-HT2B receptor and hence serves a valuable starting point for the design of potent 5-HT2B antagonist.

Aporphines as 5-HT7 Ligands

As mentioned previously, compound 14 was identified by Hedberg and co-workers as a potent 5- HT1A ligand. An expanded screening of 14 revealed it to have a decent affinity at the 5-HT7 receptor and accordingly a systematic structure activity relationship study was initiated [46]. Incorporation of symmetrically di-ortho-substituted C-11phenyl rings resulted in compounds (compound 78 and 79) with pronounced decrease in affinity at the 5-HT7 receptor as well as 5-HT1A and D2 receptors. These substitutions however resulted in increased selectivity for the 5-HT7 receptor over 5-HT1A receptor. A similar trend in selectivity was observed when unsymmetrical di-ortho-substituted C-11 phenyl rings were incorporated. Compound 80 in particular was the most potent compound identified in this series. Interestingly compound 81 (an atropisomer of compound 80) was 5 fold less potent than 80 (Figure 8).


Figure 8: Structure of 82.

Similarly SAR studies on the rigidified 1, 11 methyleneaporphine scaffold produced compounds having a diverse and interesting range of affinities at the 5-HT7 receptor [47]. When compared to compound 82, the rigidified methylene derivative 83 displayed 12 fold higher affinity at the 5-HT7 receptor. This clearly indicated that the added strain of the rigidified methylene group was beneficial in increasing the 5-HT7 receptor affinity. Introduction of substituents on the methylene carbon produced interesting pharmacological effects. For example, compound 84 (6aR, 12R - OH group above the plane) displayed higher affinity than compound 85 (6aR, 12S - OH group below the plane). Adding a methyl group of C-12 resulted in an opposite trend. Thus compound 87 (6aR, 12S – OH group below the plane) displayed more affinity than compound 86 (6aR, 12R – OH group above the plane) (Tables 6 and 7).

Compound R1 R2 Ki(nM)
      5-HT7 5-HT1A D2
78 OH OH 13 554 2030
79 OTf OTf 708 >10000 2260
80 Me CN 20.80 778 2470
81 CN Me 3.79 142 498
14 H H 9.78 1.80 233

Table 6: Binding affinity data of C-11 phenyl aporphine analogues.

Compound R1 R2 Ki(nM)
      5-HT7 5-HT1A D2
83 H H 6.90 40.70 83.20
84 OH H 13.50 31 23.80
85 H OH 103 1210 215
86 OH Me 27.70 315 182
87 Me OH 4.30 61.50 26
82 - - 88 80 527

Table 7: Binding affinity data of 1, 11 rigidified aporphine analogues

In a more recent study, our group reported the evaluation of a series of C9 alkylated aporphine derivatives [48]. The design of these compounds was based on the structure of compound 88, which was previously reported to have 5-HT1A and 5-HT7 receptor affinity [49]. Most of these compounds displayed moderate to good affinity for the 5-HT7 receptor with a moderate selectivity over the 5- HT1A receptor. Overall it was found that a C9 phenolic OH group is not absolutely required for 5- HT7 receptor affinity, and that small alkoxy groups are well tolerated at this position (Table 8).

Compound R Ki(nM)
    5-HT7 5-HT1A 5-HT2A
88 H 20 314 -
89 Me 43 171 966
90 Et 69 506 818
91 n-butyl 15 153 268
92 CyclopropylMe 22 224 582
93 Allyl 20 361 383
94 p-bromobenzyl 54 102 418

Table 8: Binding affinity data of C9 alkoxy aporphine analogues.


Aporphine alkaloids have been studies in much detail over the past two decades mainly at the dopaminergic and 5-HT1A receptor systems. Much of the recent work has focused on the evaluation of aporphine alkaloids as ligands at the 5-HT2A and 5-HT7 receptor system. This review concentrated on the SAR of aporphine alkaloids at the 5-HT1A, 5-HT2A, 5-HT2B and 5-HT7 receptor subtypes. At the 5-HT1A receptor, various alkyl substitutions are tolerated at the C-10 and C-11 position, where a lipophilic pocket seems to interact with this substituents. Long chain alkyl substitutions at the C1 position were beneficial for affinity at the 5-HT2A receptor. Several rigidified aporphine alkaloids displayed enhanced affinity at the 5-HT7 receptor. Although several analogues of aporphine alkaloids have been prepared and evaluated at these receptors, in general most of the SAR study has been limited to specific positions for particular receptor subtypes (for example C10 and C11 for 5-HT1A and 5-HT7, C1 and C2 for 5-HT2A). Considering the fact that small modifications on the aporphine scaffold produces diverse range of pharmacological actions, the unexplored chemical space around the aporphine template needs to be systematically evaluated. Furthermore, a truly selective aporphine alkaloid for either of these targets still needs to be discovered. Such a discovery will help medicinal chemist understand the often complex CNS receptor signaling process involved in the progression of several neuropsychiatric disorders and hence design better drugs targeting such disorders.


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