Aporphine Alkaloids As Ligands for Serotonin Receptors

l ch cina em di is e tr Kapadia and Harding, Med chem (Los Angeles) 2016, 6:4 M y Medicinal chemistry DOI: 10.4172/2161-0444.1000353 ISSN: 2161-0444 Review Article Open Access 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 Abstract 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 mono- potent 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. Keywords: Aporphine; Central nervous system; Ligands; Alkaloids Introduction 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 Figure 2: (R) – Apomorphine. Annonaceae, Lauraceae, Monimiaceae, Menispermaceae, Hernandiaceae and other plant families [1] (Figure 1). (Positron Emission Tomography) and SPECT (Single Photon Emission Both naturally occurring and synthetic aporphine alkaloids possess Computed Tomography) radiotracers for brain imaging studies diverse range of pharmacological actions. Figure 1 shows the basic [17]. Aporphines are also reported as inhibitors of the enzyme Acetylcholinesterase and as antagonists of the α -adrenergic aporphine skeleton [2]. 1 receptor and thus have potential therapeutic role in the treatment of Alzheimer’s Pharmacological Effects of Aporphine Alkaloids disease and hypertension respectively [18-21]. Aporphine alkaloids exhibit a plethora of effects within the Thus the aporphine scaffold can be considered a privileged scaffold Central Nervous System (CNS). There are a number of aporphine for the design of CNS ligands. A majority of the work in the early alkaloids reported as ligands at dopamine and serotonin receptors 1990s has focused on the design of aporphine alkaloids as ligands for Ligands at the D and D dopamine receptor subtypes have a [1,3]. 1 2 the dopamine receptor system. In terms of the serotonin receptors, potential role in the treatment of Parkinson’s disease, schizophrenia, mostly been studied as ligands at the 5-HT receptor. aporphines have 1A Attention Deficit Hyperactivity Disorder (ADHD), depression, and Some of this previous work has been nicely summarized in previously drug abuse [4-6]. In fact, (R) - Apomorphine (2) which is considered to published reviews [1,3]. 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 Aporphine as 5-HT1A Ligands 5-HT serotonin receptor subtype have been useful in the treatment 1A The first aporphine alkaloid reported as a selective serotonin ligand of anxiety, schizophrenia and depression [8-11] (Figure 2). was reported by Canon and co- workers in 1988 [22]. The R( ) - (-) - Aporphines are also ligands at the 5-HT and 5-HT receptors. 10-Methyl-11-hydroxyaporphine (R - 3) (Figure 3) was originally 2A 7 Selective 5-HT ligands have promising applications in the treatment designed as a dopamine receptor ligand. Surprisingly R - 3 displayed 2A of drug abuse and insomnia. Mixed dopamine/5-HT serotonergic agonistic activity with a high degree of selectivity for 2A ligands the 5-HT receptor. Further studies revealed that the S isomer of 3 have potential for the alleviation of symptoms of depression and 1A (S - 3) was an antagonist at the 5-HT receptor [23]. This trend of schizophrenia [12,13]. Ligands at the 5-HT receptor have shown 1A 7 enantiomers having opposing promising results for the treatment of sleep disorders, migraine pharmacological effects was found to be consistent with other aporphine enantiomers displaying opposing and depression [14-16]. Moreover aporphines possessing affinity effects at the dopaminergic receptors (Figure 3). at the dopamine and serotonin receptors have potential use as PET *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: [email protected] Received 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 Figure 1: Basic aporphine skeleton. original author and source are credited. Med chem (Los Angeles) Volume 6(4): 241-249 (2016) - 241 ISSN: 2161-0444 Med chem (Los Angeles), an open access journal 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 In order to probe the role of the C-10 methyl group compound 4 and co-workers by the evaluation of a series of C-10 substituted that lacked a C-10 methyl group was evaluated for dopaminergic and aporphine compounds [29]. Substitution of bulky groups at the C-10 serotonergic activity. Both the enantiomers of compound 4 were found position (compound 9, 10, 11 and 12) resulted in dramatic loss of to possess dopaminergic activity but lacked any appreciable serotonin affinity for the 5-HT 1A receptor whereas small alkyl group substituents 5-HT activity [24]. 1A This clearly indicated a significant role of the (compound 13) were well tolerated, thus confirming the existence of C-10 methyl group towards the enhanced 5-HT the lipophilic “methyl” pocket, which is able to accommodate only 1A affinity of 3 (Figure 4). small groups. It was further shown that both the C-10 methyl and C-11 In contrast to the previously observed strict requirement of a C-11 required for affinity at the 5-HT hydroxyl group in compound 3 are 1A hydroxyl/C-10 methyl substitution, a series of mono C-11 substituted receptor. This was evident from the observed lower affinity of the aporphine compounds (14, 15 and 16) were found to have good affinity mono methylated compound 5 [25]. Furthermore, the high affinity as well as selectivity for the 5-HT receptors [29]. Based on molecular 1A at the 5-HT receptor of modeling 1A compound 3 is unique and specific to an studies substituents at the C-11 position interacted in a 11-hydroxy, 10-methyl substitution pattern. Having this substitution at manner that was different from thepreviously seen hydrogen bond interaction of the C-11 hydroxyl group with the 5-HT receptor. other positions (such as in compounds 6 and 7) resulted in complete 1A In at the 5-HT receptor [26]. High affinity for the 5-HT loss of affinity 1A 1A the case of C-11 substituents, significant interactions were seen with receptor was also observed in the case of compound 8, which possesses a pocket lined by Ser168, Met172, Thr196. Ser199, Thr200, Phe362, a similar ortho hydroxyl/hydroxyl methyl substitution [27] (Figure 5). Ala365 and Leu366. This indicated that the proposed methyl pocket was much larger, and suitable C-11 substituents could interact with it. Based on molecular docking studies, the C-11 hydroxyl group This hypothesis of a larger lipophilic pocket was further confirmed by makes a hydrogen bond interaction with Ser198 and Ser193 residues of Zhang et al. by the synthesis and evaluation of compounds 17, 18 and the 5-HT and D receptors respectively. The main difference however 1A 2 19 that lacked a C-11 hydroxyl group yet displayed high affinity at the is the interaction of the C-10 methyl group wherein it interacts with 5-HT receptor [30]. the 5-HT receptor, which is not available in 1A a lipophilic pocket in 1A the case of the D receptor. The absence of a similar lipophilic pocket 2 Other reported SAR studies include the evaluation of C10 around the C-10 methyl group in the D receptor explained the high 2 substituted long chain carbamate (20 and 21) or amide (22 and 23) selectivity of 3 for the 5-HT receptor over the D receptor [28]. aporphines [31]. These compounds displayed only moderate affinity at 1A 2 5-HT receptor as shown in Table 1. Similarly limited studies have the 1A The existence of this lipophilic pocket was further tested by Hedberg been done at other positions of the aporphine scaffold with regards to the 5-HT affinity. Zhang and co-workers reported the 1A evaluation of C-2 substituted aporphine compounds (24, 25 and 26) which did appreciable affinity at the 5-HT receptor, although the not show any 1A number of compounds studies are too less to make a general conclusion [32] (Figure 6). Although an N-methyl group is not absolutely required for 5-HT 1A affinity as indicated by compounds 27 and 28, an increase in affinity and selectivity for the 5-HT receptor was observed 1A when the size of the substituent was decreased to a methyl or a hydrogen group (Table 1). Aporphines as 5-HT2A Ligands Figure 3: Structure of R and S enantiomers of compound 3. Majority of the work of aporphine alkaloids as ligands at the 5-HT receptor has mainly focused 2A on the natural alkaloid nantenine.

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