Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5-HT2A Receptors

DOI : 10.1002/cmdc.200800133 Structure–Activity Relationships of Phenylalkylamines as Agonist Ligands for 5-HT 2A Receptors Antoni R. Blaazer,* [a] Pieter Smid, [b] and Chris G. Kruse* [a, b] Introduction Wide-ranging physiological processes are mediated through the serotonin (5-hydroxytryptamine, 5-HT, 1) system. 5-HT and its receptors are scattered throughout the body. Dysfunction has been implicated in cardiovascular and digestive disorders as w

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  DOI: 10.1002/cmdc.200800133 Structure–Activity Relationships of Phenylalkylamines asAgonist Ligands for 5-HT 2A Receptors Antoni R. Blaazer,* [a] Pieter Smid, [b] and Chris G. Kruse* [a, b] Introduction Wide-ranging physiological processes are mediated throughthe serotonin (5-hydroxytryptamine, 5-HT, 1 ) system. 5-HT andits receptors are scattered throughout the body. Dysfunctionhas been implicated in cardiovascular and digestive disordersas well as numerous psychiatric disorders. [1] Pharmacologicalmanipulation of the 5-HT system is believed to have therapeu-tic potential, and therefore the subject of intense research. [2] There are seven distinct families of 5-HT receptors (5-HT 1–7 ),and there is molecular and functional evidence for the exis-tence of at least 14 different mammalian subtypes. [3] With theexception of the 5-HT 3 receptor, a ligand-gated ion channel, all5-HT receptors are G protein-coupled receptors (GPCRs). [3,4] The5-HT 2 receptor family has three known subtypes, 5-HT 2A , 5-HT 2B and 5-HT 2C , [4,5] with ~ 46–50% sequence identity. [1] Moreover,the transmembrane domains of the 5-HT 2A and 5-HT 2C recep-tors share 80% sequence identity, suggesting similar pharma-cological profiles. [6] In the central nervous system (CNS), 5-HT 2A receptors are pri-marily found in cortical and forebrain areas, various brainstemnuclei, and the hippocampus. [7] The cellular localization of 5-HT 2A receptors is primarily on the dendrites [8,9] of cortical pyra-midal glutamatergic projection neurons, [10,11] local GABAeric in-terneurons, [12] and on cholinergic neurons. [13–15] A proportion of 5-HT 2A receptors is believed to be located presynaptically on,most probably, monoamine axons. [9] Glial 5-HT 2A receptorshave been identified also. [9,16] Peripherally, the 5-HT 2A receptoris found in platelets, vascular smooth muscle cells, and oculartissue. [17–19] In contrast, the 5-HT 2B receptor is primarily found inthe periphery, such as the rat stomach fundus, and caninelungs and smooth muscles. [3,4,20] Furthermore 5-HT 2B receptorsare found in the hearts of primates and rats. [21] The murine 5-HT 2B receptor is expressed in the stomach, intestine, pulmona-ry smooth muscles, myocardium, and the brain, most notablycerebellar Purkinje cells. [22] Distribution of the 5-HT 2C receptoris primarily limited to the CNS. [1] 5-HT 2C mRNA is broadly dis-tributed throughout numerous brain regions; this receptorsubtype is believed to be the principal 5-HT receptor in thebrain. [23] Physiological Roles and Therapeutic Potentialof 5-HT 2 Receptors Given their distribution pattern, 5-HT 2 receptors have diversephysiological roles. Central 5-HT 2A receptors modulate GABAer-gic and glutamergic neurotransmission. [17] Activation of 5-HT 2A receptors stimulates the secretion of various hormones. [24] 5-HT 2A receptors play a physiological role in working memory, [25] the regulation of cognitive states, and associative learning. [26] Moreover, 5-HT 2A receptors influence neuronal plasticity  Agonist activation of central 5-HT  2A receptors results in diverse ef-fects, such as hallucinations and changes of consciousness.Recent findings indicate that activation of the 5-HT  2A receptor also leads to interesting physiological responses, possibly holdingtherapeutic value. Selective agonists are needed to study the full therapeutic potential of this receptor. 5-HT  2A ligands with agonist  profiles are primarily derived from phenylalkylamines, indolealkyl-amines, and certain piperazines. Of these, phenylalkylamines,most notably substituted phenylisopropylamines, are considered the most selective agonists for 5-HT  2 receptors. This review sum-marizes the structure–activity relationships (SAR) of phenylalkyla-mines as agonist ligands for 5-HT  2A receptors. Selectivity is a cen-tral theme, as is selectivity for the 5-HT  2A receptor and for its spe-cific signaling pathways. SAR data from receptor affinity studies,functional assays, behavioral drug discrimination as well ashuman studies are discussed. [a] A. R. Blaazer, Prof. Dr. C. G. KruseSwammerdam Institute for Life Sciences, Centre for NeuroScience, University of AmsterdamKruislaan 320, 1098 SM Amsterdam (The Netherlands)Fax: (  + 31)610-059-548E-mail:  [b] Dr. P. Smid, Prof. Dr. C. G. KruseSolvay Pharmaceuticals, Research LaboratoriesC. J. van Houtenlaan 36, 1381 CP Weesp (The Netherlands)Fax: (  + 31)294-477-148E-mail: ChemMedChem 2008  , 3, 1299–1309  2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 1299  through brain-derived neurotrophic factor (BDNF)-mediatedprocesses. [27] Intra-ocular pressure (IOP) is regulated by 5-HT 2A receptors. [18,19] Peripheral 5-HT 2A receptors mediate diverse pro-cesses such as vasoconstriction and platelet aggregation. [1,28] 5-HT 2B receptors mediate neural tube morphogenesis in theembryo, [29] and are important in the development of the cardi-ovascular system. [30,31] The 5-HT 2C receptor is involved in di-verse processes such as locomotor activity, anxiogenesis, andneuro-endocrine functions. [17] Moreover, the 5-HT 2C receptorregulates various aspects of feeding and food intake, [32] and isimplicated in sexual dysfunction in males. [33,34] Both 5-HT 2A and5-HT 2B receptors were found to mediate liver regeneration in apartial hepatectomy model. [35] Drugs that target 5-HT 2 receptors are used in the treatmentof various psychiatric disorders, including depression, [36] anxi-ety, [37–39] obsessive-compulsive disorders, [40] and schizophre-nia. [41,42] Many antipsychotic drugs are 5-HT 2A receptor inverseagonists or antagonists. [43,44] Activation of the 5-HT 2A receptorby agonist psilocybin ( 2 ) produces schizophrenia-like psychoticsymptoms in humans, which are significantly reduced by selec-tive 5-HT 2A antagonists. [45] Psychotomimetic effects of halluci-nogenic drugs such as psilocybin ( 2 ), d  -lysergic acid N  , N  -dieth-ylamide (LSD, 3 ), and mescaline ( 4 ) are primarily mediated by5-HT 2A receptors. [46–49] Mystical-type experiences of sustainedpersonal meaning have been reported to result from the useof psilocybin in a controlled setting. [50] Elucidation on howthese experiences arise in the brain could potentially havetherapeutic possibilities. [50] The reduction in IOP by 5-HT 2A ago-nists has recently been recognized as an efficient treatment forocular hypertension and glaucoma. [18,51,52] Agonist activation of 5-HT 2A and 5-HT 2B receptors results in liver regeneration, [35] however clinical efficacy in liver regeneration following trans-plantation remains to be demonstrated. [53,54] 5-HT 2B receptorantagonists can be used to treat anxiety disorders, however,their application is limited because of the role this receptorplays in embryogenesis. [17] Drugs targeting both 5-HT 2B and 5-HT 2C receptors can be used to treat migraines. [42,55] Drugs mod-ulating 5-HT 2C activity are applicable in the treatment of obesi-ty, erectile dysfunction and anxiety disorders. [17,32] 5-HT 2 Receptor Agonist Ligands Ligands for 5-HT 2 receptors belong to structurally diversechemical classes, most notably indolealkylamines, phenylalkyla-mines, arylpiperazines, alkylpiperidines, alkylpiperazines, poly-cyclic/tricyclic agents, among others. [56] 5-HT 2 receptor subtypeligands have been developed. [17,57,58] Agonist activation of 5-HT 2 receptors has been the subject of recent studies, indicatinga growing interest in the therapeutic potential underlying acti-vation of this class of receptors. [18,32,35,36,38,40,50] 5-HT 2 receptoragonists generally show little subtype selectivity, however,some selective agonists have been designed for 5-HT 2B and 5-HT 2C receptors. [32,59,60] The identification of agonists with 5-HT 2A receptor subtype selectivity lags behind, and the need for theirdevelopment has been acknowledged. [3,4,17] Agonists selectivefor the 5-HT 2A receptor and its associated signaling pathwaysare needed to research the full therapeutic potential of this re-ceptor.5-HT 2A receptor agonists and partial agonists are primarily in-dolealkylamines and phenylalkylamines. [61] Certain piperazineshave also been classified as agonists. [62] Based on their struc-tures, the indolealkylamines can be subdivided into trypta-mines, ergolines and b -carbolines, and he phenylalkylamineclass includes phenethylamines and phenylisopropylamines(amphetamines). Indolealkylamines generally show little sub-type selectivity, binding multiple 5-HT receptor subclasses. [63] The most selective agonists for 5-HT 2 receptor subtypes arefound in the phenylalkylamine class, most notably the substi-tuted phenylisopropylamines. The structure–activity relation-ships (SAR) have been extensively studied generating a vastnumber of phenylalkylamines with 5-HT 2A binding potentialand functional activity. [64–67] The purpose of this review is tosummarize the SAR of the phenylalkylamines as agonist li-gands for the 5-HT 2A receptor, focusing on subtype and func-tion selectivity. Signaling pathways, pharmacological methods,site-directed mutagenesis and molecular modeling studies rel-evant for 5-HT 2A receptor research are described. 5-HT 2A Receptor Signaling and FunctionalSelectivity The concepts used in receptor pharmacology are constantly re-vised to fully describe the complexity of GPCR signaling. [68,69] Ligands are believed to induce conformational changes in theGPCR resulting in differential activation of the associated signaltransduction pathways. [70,71] Moreover, cellular conditions arerecognized as an important factor in determining drug action,and the classical concept of “intrinsic efficacy” is no longersupported. [72] Detailed knowledge of downstream signalingpathways coupled to 5-HT 2A receptors is needed to study thefunctional activity of these ligands. As a pleiotropic GPCR, the5-HT 2A receptor can couple to different G proteins, and has theability to show a broad array of responses, such as internaliza-tion and desensitization. [73,74] The ligand-induced differentialactivation of downstream signaling pathways has been givenvarious names, such as “agonist-directed trafficking of receptorstimulus”, “protean agonism” and “ligand-biased effica-cy”; [70,71,75,76] however, it has been suggested that “functionalselectivity” is the most suitable term to refer to this concept. [71] 5-HT 2A receptors coupled to heterotrimeric GTP binding pro-teins regulate a variety of cell responses (Figure 1). The 5-HT 2A receptor activates phospholipase C (PLC) and phospholipaseA 2 (PLA 2 ), and is involved in various other signaling cas-cades. [77–80] PLC- b is activated by the 5-HT 2A receptor mainlythrough coupling with G a q/11 , resulting in the release of inosi-tol-1,4,5-triphosphate (IP 3 ) and 1,2-diacylglycerol (DAG)through lipid hydrolysis of phosphatidylinositol-4,5-biphos-phate (PIP 2 ). [81,82] IP 3 is responsible for Ca 2 + release from intra-cellular stores, whereas DAG is involved in protein kinase C(PKC) activation. [83–86] Conversion of DAG to endocannabinoid2-arachidonoylglycerol (2-AG) by DAG lipase (DGL) [87,88] isknown to occur following 5-HT 2A receptor activation in NIH 3T3cells, [89] adding another level of complexity. 1300  2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim ChemMedChem 2008  , 3, 1299–1309 MED A. R. Blaazer, P. Smid, and C. G. Kruse  The 5-HT 2A receptor is responsible for PLA 2 activation andsubsequent arachidonic acid (AA) release through two parallelsignaling cascades. [90,91] The Ras-Raf-MEK-ERK signaling path-way is activated through G a i/o , leading to phosphorylation of cPLA 2 by ERK1,2. The other cascade involves a G a 12/13 -RhoA-p38 pathway, which results in p38 mitogen-activated proteinkinase (MAPK)-mediated phosphorylation of PLA 2 . [91] The 5-HT 2A receptor can also couple with monomeric G-protein ADP-ribo-sylation factors (ARF) resulting in phospholipase D (PLD) activi-ty. [92] Rho proteins (e.g. RhoA) are involved in PLD activationalso, in which PKC may function as a modulator. [93] PLD promo-tion, notably through ARF1, leads to hydrolysis of phosphati-dylcholine (PC) to yield phosphatidic acid (PA) and choline. [94,95] PA is involved in regulation of numerous downstream cellularprocesses.As a consequence of the acute pharmacological responses just described, 5-HT 2A receptor activation results in alteredgene expression. Activation of 5-HT 2 receptors by known ago-nist DOI ( 17 ) has been found to induce expression of immedi-ate early genes c-fos , ngf1c , tis1 and arc in various rat brain re-gions, whereas antagonists were able to block the expressionpatterns. [96–98] The expression of Fos in the rat cortex elicitedby DOI is mediated through 5-HT 2A receptors; treatment with aselective 5-HT 2A antagonist completely blocked the responsewhile treatment with a 5-HT 2C antagonist did not influence ex-pression levels. [99] The genomic response to LSD ( 3 ), a halluci-nogenic ergoline with a broad pharmacological profile, [100,101] has also been studied. [102,103] More recent work reported theuse of transcriptome fingerprints elicited by 5-HT 2A ligands as atool to distinguish between hallucinogenic and non-hallucino-genic agonist effects; results indicated that c-fos expressionwas a response to general 5-HT 2A receptor activation, while in-duction of  erg-1 , erg-2 and period-1 resulted from activation bybehaviorally active agonists. [104] This is hypothesized to resultfrom the ability of ligands to differentially regulate intracellularsignaling pathways. [105] Pharmacological Methods The effects of structural modifications to ligands can be evalu-ated by several pharmacological methods, of which binding af-finity studies and functional assays are most relevant for theSAR of 5-HT 2A receptors. Binding affinities can be determinedby radioligand competition assays using rat brain homogenateor cloned human receptors. [106] Several antagonist and agonistradioligands, with known binding properties, are available forcompetition assays at the 5-HT 2A receptor. [107–109] Agonists andantagonists display different affinities for various receptorstates, [110] an observation accounted for by receptor theo-ries. [70,111–113] Functional assays measure the physiological response elicit-ed by a drug in target cells or tissues. [114] Efficacy can be de-fined as the extent to which a ligand causes the receptor tochange its behavior towards the cell. [74] Several functional re-sponses can be used to study the activation of 5-HT 2 receptorsin isolated tissue. [28] Historically, smooth muscle contraction inisolated vasculature was used as a model for receptor activa-tion. Recent studies have used intracellular signals from down- Figure 1. Graphical representation of the known 5-HT 2A signaling pathways. The 5-HT 2A receptor couples to various downstream effectors enabling diversecellular responses following receptor activation. Some of the mediating proteins (MP) are omitted for clarity. Mediating proteins (MP1) in the G a 12/13 -RhoA-p38 pathway most probably are PKN, MEKK, MKK3/6 and MKK4. [89] Shc, Grb2 and SOS are the proteins mediating (MP2) the Ras-Raf-MEK1,2-ERK1,2 pathway.Receptor regulatory pathways (e.g. phosphorylation; internalization; desensitization) following agonist activation, are not shown. Note: the localization of pro-teins and messengers in this Figure does not represent their localization in a functional cell. ChemMedChem 2008  , 3, 1299–1309  2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 1301 Phenylalkylamines as 5-HT  2A Receptor Agonists  stream pathways, such as those described above, to measurereceptor activation. [71] In vivo 5-HT-targeting drug evaluation has largely been car-ried out in rodents, where 5-HT mimetics cause a state of be-havioral excitation, described as serotonin syndrome. [28] Thebehavioral effects of phenylalkylamines have been investigatedin drug discrimination (DD) studies. [115] Rats are trained to dis-criminate between injections of the training drug and saline ina two-lever DD task. [116] Substitution of the training drug, orstimulus generalization, suggests that a drug with effects simi-lar to the training drug has been administered. [61] The potencyof a drug, and the effective dose (ED) can also be establishedin this paradigm. Drug-elicited behaviors, such as the head-twitch response, are studied as well. [115] A fair number of phe-nylalkylamines have been examined in humans, and dosagedata is available. [117] Numerous factors unrelated to the studyof receptor-ligand interactions can influence the in vivo effectsof a drug, hence the direct comparison of receptor bindingdata with in vivo data is tentative. Site-Directed Mutagenesis and Molecular Mod-eling Site-directed mutagenesis studies have been carried out toidentify the structural requirements for interactions in ligand–receptor complexes, [118] and these studies have been reviewedin depth. [62,82,119] Briefly, a protonated amine moiety is believedto anchor the ligand in the transmembrane helix 3 (TMH3)domain through an ionic interaction with the carboxylategroup of Asp155 A C H T U N G T R E N N U N G (3.32). [120] Phe340 A C H T U N G T R E N N U N G (6.52) is essential for agonistbinding and recognition. It is involved in stabilizing the aro-matic ring of ligands, and mutations at this residue cause adramatic decrease in agonist affinity and efficacy. [121–123] Posi-tions 5.42, 5.43, and 5.46 of transmembrane helix 5 (TMH5)play important roles in ligand recognition and specificity. [118] The Ser159 A C H T U N G T R E N N U N G (3.36) residue interacts with the ligand through hy-drogen bonding; this interaction may account for the differingfunctional effects of structurally similar indolealkylamines. [124] Other serine residues have been found to influence agonistbinding as well. [125–127] Three-dimensional templates based on a bacteriorhodopsinmodel were able to explain some of the results from mutagen-esis studies. [62,128,129] Comparative molecular modeling of ligand–GPCR interactions was greatly facilitated by the elucida-tion of the bovine rhodopsin crystal structure, [130] and subse-quent refinements. [131–133] The key role of Asp155 A C H T U N G T R E N N U N G (3.32) as a ter-minal amine anchor is in agreement with previous mutagene-sis data. [134] Molecular modeling of the 5-HT 2A receptor, togeth-er with detailed site-directed mutagenesis studies, suggests ahydrophobic binding pocket surrounding the ligand, with aro-matic residues Trp151 A C H T U N G T R E N N U N G (3.28), Phe243 A C H T U N G T R E N N U N G (5.47), Phe244 A C H T U N G T R E N N U N G (5.48),Trp336 A C H T U N G T R E N N U N G (6.48), Phe339 A C H T U N G T R E N N U N G (6.51), Phe340 A C H T U N G T R E N N U N G (6.52), Trp367 A C H T U N G T R E N N U N G (7.40), andTyr370 A C H T U N G T R E N N U N G (7.43). [135,136] Polar moieties within agonists may interactwith Ser159 A C H T U N G T R E N N U N G (3.36), Thr160 A C H T U N G T R E N N U N G (3.37), Ser239 A C H T U N G T R E N N U N G (5.43), Ser242 A C H T U N G T R E N N U N G (5.46),and Asn343 A C H T U N G T R E N N U N G (6.55) from the 5-HT 2A binding site. [124,137] Dockingstudies using a human 5-HT 2A receptor homology-basedmodel, created from an in silico activated bovine rhodopsincrystal structure, confirmed these interactions. [137] Different binding orientations of DOM ( 15 ) and 5-HT ( 1 )have been suggested using a rat 5-HT 2A receptor model basedon the frog rhodopsin projection map. [135] The molecular mech-anism of partial agonism and the relative efficacy of 5-HT 2A re-ceptor ligands are determined by the ligand interaction withSer159 A C H T U N G T R E N N U N G (3.36) and Ser242 A C H T U N G T R E N N U N G (5.46). [138] It was concluded that spe-cific interactions in TMH3 and TMH5 are responsible for thevarying degrees of receptor activation. Recently, Ser239 A C H T U N G T R E N N U N G (5.43)was shown to be more critical for agonist binding and functionthan Ser242 A C H T U N G T R E N N U N G (5.46) within TMH5. [139] The oxygen atom at the 5-position of phenylalkylamines forms a hydrogen bond withSer239 A C H T U N G T R E N N U N G (5.43). Ser242 A C H T U N G T R E N N U N G (5.46) is believed to act as a hydrogenbond acceptor, interacting with N  (1)H of the indole ring in in-dolealkylamines, but not phenylalkylamines. Classic Phenylalkylamines Phenylalkylamines 4 – 24 were used in the early SAR studies. Re-search focused on the nature of substituent X, para to the al-kylamine side chain. In the case of 3,4,5-substituted phenethyl-amine, escaline ( 5 ) is 5–8 times more potent in humans thanmescaline ( 4 ). [140] [ 125 I]DOI ( 17 ) radioligand competition studiesusing cloned human 5-HT 2A receptors further confirm this find-ing; the affinity of  5 ( K  i = 216 n m ) exceeded the affinity of  4 ( K  i = 551 n m ) for 5-HT 2A receptors. [141] It has been noted thathomologation beyond n -propoxy leads to diminished halluci-nogenic activity of this series in humans. [142] Replacing thealkoxy substituents at the 4-position with alkylthio substituentsleads to a further increase in potency. The potency of 4-thio-mescaline ( 6 ) is an order of magnitude greater than the parentcompound 4 , and 4-thioescaline ( 7 ) is three times more potentthan 5 . [142,143] The same pattern is seen in 2,4,5-substituted phenethyla-mines. For example, replacement of the 4-methoxy group inTMPEA ( 8 ) by a 4-methylthio group (2C-T, 9 ) leads to a large in-crease in potency in humans. [117] Halogen and alkyl para -substi-tuted phenethylamines, including 2C-D ( 10 ), 2C-B ( 11 ) and 2C-I( 12 ), are generally the most potent compounds of thisseries. [117,144,145] Homologation of the 4-alkyl group of 2C-D ( 10 )results in more potent agents such as the 4-ethyl ( 13 , 2C-E),and 4- n -propyl ( 14 , 2C-P) analogues. [145] a -Methylation of the phenethylamines to their correspond-ing phenylisopropylamines leads to the most potent com-pounds, such as DOM ( 15 ), DOB ( 16 ), and DOI ( 17 ). [146–148] A sig-nificant increase in potency was observed from compound 10 (ED 50 = 5.6 m  molkg À 1 ) to ( Æ )- 15 (ED 50 = 1.8 m  molkg À 1 ) in DDstudies, [149] and in human clinical studies. [117,144] However, an af-finity study using rat brain [ 3 H]ketanserin labeled 5-HT 2 sitesshowed that the affinity of compound 10 ( K  i = 110 n m ) is ap-proximately equal to the affinity of its phenylisopropylamineanalogue ( Æ )- 15 ( K  i = 100 n m ). [150] Similarly, the binding affinityof compound 18 (DOTFM, K  i = 1.5 n m ) was close to that of itsphenethylamine congener ( K  i = 1.1 n m ). [151] A number of hy-potheses account for the discrepancy between the binding af-finities and in vivo potency of these compounds. The a -methyl 1302  2008 Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim ChemMedChem 2008  , 3, 1299–1309 MED A. R. Blaazer, P. Smid, and C. G. Kruse
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