2-Phenethylamines in Medicinal Chemistry: A Review

A concise review covering updated presence and role of 2-phenethylamines in medicinal chemistry is presented. Open-chain, flexible alicyclic amine derivatives of this motif are enumerated in key therapeutic targets, listing medicinal chemistry hits and appealing screening compounds. Latest reports in discovering new bioactive 2-phenethylamines by research groups are covered too.


Introduction
The 2-phenethylamine motif is widely present in nature, from simple, open-chain structures to more complex polycyclic molecular arrangements. The importance of this moiety is probably best exemplified by the endogenous catecholamines dopamine, norepinephrine and epinephrine (an example of open-chain 2-phenethylamines), exhibiting a central role in dopaminergic neurons, which play a critical role in voluntary movement, stress or mood [1]. Several naturally occurring alkaloids, i.e., morphine, (S)-reticuline or berberine, embedded in the 2-phenethylamine unit form more complex cyclic frameworks derived from its natural biosynthetic pathways ( Figure 1).

Introduction
The 2-phenethylamine motif is widely present in nature, from simple, open-chain structures to more complex polycyclic molecular arrangements. The importance of this moiety is probably best exemplified by the endogenous catecholamines dopamine, norepinephrine and epinephrine (an example of open-chain 2-phenethylamines), exhibiting a central role in dopaminergic neurons, which play a critical role in voluntary movement, stress or mood [1]. Several naturally occurring alkaloids, i.e., morphine, (S)-reticuline or berberine, embedded in the 2-phenethylamine unit form more complex cyclic frameworks derived from its natural biosynthetic pathways ( Figure 1). Additionally, in addition to their prominent therapeutic applications, it is worth mentioning the recreational use of a long list of alkaloids incorporating the aforementioned moiety ("designer drugs") [2], responsible for drug abuse-related conditions [3][4][5][6][7][8]. Surprisingly, the literature lacks a comprehensive summary that bundles up 2-phenethylamine-based structures and known therapeutic targets, including basic hits or advanced Additionally, in addition to their prominent therapeutic applications, it is worth mentioning the recreational use of a long list of alkaloids incorporating the aforementioned moiety ("designer drugs") [2], responsible for drug abuse-related conditions [3][4][5][6][7][8]. Surprisingly, the literature lacks a comprehensive summary that bundles up 2-phenethylamine-based structures and known therapeutic targets, including basic hits or advanced leads. Pairing these will present an appealing opportunity to both new and experienced researchers to summarize 2-phenethylamines target binding and therapeutic scope, as well as selectivity/antitarget issues. Considering all these, a review covering the medicinal chemistry landscape is presented here as a brief, central resource linking up 2-phenethylamine hits and receptors. From the structural point of view, 2-phenethylamines present a vast therapeutic chemical space, not just as is, but considering different substitutions, functional group decorations, ring enclosures or heteroaromatic analogues. Describing such a massive quantity of scaffolds with the phenethylamine resemblance is beyond the scope of this review and more, such asly requires a dedicated book. For this reason, the present review covers only structures where there is an alicyclic amine (Figure 2, blue examples), clustering them all under the 2-phenethylamine label. The authors believe that such cases as 2-heteroaryl ethylamines or cyclic amines, despite presenting 2-phenethylamine resemblance, represent other categorized entities (i.e., tetrahydroisoquinolines or 3-phenyl-pirrolidines examples) on their own, worth independent review ( Figure 2, red examples). This review also covers those 2-phenethylamines where the phenyl ring is condensed with a heteroaryl ring, as the primary motif ring is a phenyl one. leads. Pairing these will present an appealing opportunity to both new and experienced researchers to summarize 2-phenethylamines target binding and therapeutic scope, as well as selectivity/antitarget issues. Considering all these, a review covering the medicinal chemistry landscape is presented here as a brief, central resource linking up 2-phenethylamine hits and receptors. From the structural point of view, 2-phenethylamines present a vast therapeutic chemical space, not just as is, but considering different substitutions, functional group decorations, ring enclosures or heteroaromatic analogues. Describing such a massive quantity of scaffolds with the phenethylamine resemblance is beyond the scope of this review and more, such asly requires a dedicated book. For this reason, the present review covers only structures where there is an alicyclic amine ( Figure 2, blue examples), clustering them all under the 2-phenethylamine label. The authors believe that such cases as 2-heteroaryl ethylamines or cyclic amines, despite presenting 2-phenethylamine resemblance, represent other categorized entities (i.e., tetrahydroisoquinolines or 3phenyl-pirrolidines examples) on their own, worth independent review ( Figure 2, red examples). This review also covers those 2-phenethylamines where the phenyl ring is condensed with a heteroaryl ring, as the primary motif ring is a phenyl one. This review is divided in sections covering those molecular targets where 2-phenethylamines were found to be biologically relevant. Medicinal chemistry leads and stateof-the-art research on novel molecules are described here.

2-Heteroaryl ethylamines
Constrained scaffolds featuring an amine embedded in a (poly)cycle This review is divided in sections covering those molecular targets where 2phenethylamines were found to be biologically relevant. Medicinal chemistry leads and state-of-the-art research on novel molecules are described here. Based on these catecholamines, several studies were performed to investigate the effect of chirality, further functionalization, and activity on different derivatives [25][26][27][28][29][30][31]. This later triggered the elaboration of many derivatives conserving the 2-phenylethyl moiety, which have been frequently used in the context of medicinal chemistry as tool compounds ( Figure 5, Table 1).

β-Adrenergic Receptors
Close to the previously described α-type, the β-adrenergic receptors are also activated by catecholamines norepinephrine and epinephrine. There are three receptor subtypes (β1, β2 and β3) that are implicated in diverse cardiovascular and pulmonary functions [53,54], leading to a vast ligand chemical space ( Figure 6, Table 2) to treat cardiogenic shock, heart failure, asthma, overactive bladder (agonists), arrhythmias, hypertension (antagonists commonly known as beta blockers) [55].

Aldose Reductase
ALR2 aldose reductase is an enzyme of the polyol pathway responsible for the transformation of glucose into sorbitol, with relevant involvement in long-term diabetic complications. A series of modified 2-phenethylamines 85 comprising the insertion of aliphatic chains, aromatic rings or carboxylic acids were elaborated by Sun et al. [130]. This resulted in the obtention of a small library of derivatives with low inhibition effects towards in vitro pig kidney ALR2 ( Figure 7).
Several groups have independently used 2-phenethylamine based sulfamides and monothiocarbamates ( Figure 8) as CA inhibitors, as frequently targeting a specific CA is related to a certain syndrome or disease, such as glaucoma [134], obesity [135], or certain types of cancer [136].

Aldose Reductase
ALR2 aldose reductase is an enzyme of the polyol pathway responsible for the transformation of glucose into sorbitol, with relevant involvement in long-term diabetic complications. A series of modified 2-phenethylamines 85 comprising the insertion of aliphatic chains, aromatic rings or carboxylic acids were elaborated by Sun et al. [130]. This resulted in the obtention of a small library of derivatives with low inhibition effects towards in vitro pig kidney ALR2 ( Figure 7).

Aldose Reductase
ALR2 aldose reductase is an enzyme of the polyol pathway responsible for the transformation of glucose into sorbitol, with relevant involvement in long-term diabetic complications. A series of modified 2-phenethylamines 85 comprising the insertion of aliphatic chains, aromatic rings or carboxylic acids were elaborated by Sun et al. [130]. This resulted in the obtention of a small library of derivatives with low inhibition effects towards in vitro pig kidney ALR2 ( Figure 7).
Several groups have independently used 2-phenethylamine based sulfamides and monothiocarbamates ( Figure 8) as CA inhibitors, as frequently targeting a specific CA is related to a certain syndrome or disease, such as glaucoma [134], obesity [135], or certain types of cancer [136].

Carbonic Anhydrase
Carbonic anhydrases (CAs) are Zn-based (also Fe-based) metalloenzymes present across all living organisms of the different life kingdoms. Divided in eight different families (α, β, γ, δ, ε, ζ, η, θ, and t types), they catalyze the hydration of carbon dioxide to bicarbonate, with the purpose of transporting CO 2 to HCO 3 between tissue types, contributing to pH homeostasis, bone calcification and electrolyte transport, and ultimately participate in biogenic routes/processes, such as lipogenesis, ureagenesis or gluconeogenesis [131][132][133].
Several groups have independently used 2-phenethylamine based sulfamides and monothiocarbamates ( Figure 8) as CA inhibitors, as frequently targeting a specific CA is related to a certain syndrome or disease, such as glaucoma [134], obesity [135], or certain types of cancer [136].  [138]. Branched sulfamides integrating the 1-phenyl-2-phenethylamine scaffold, elaborated by Akıncıoğlu et al. [139] were found to be single-digit nanomolar inhibitors of both type I/II hCA ( Figure 8c).

Dipeptidyl Peptidases (DPP)
Dipeptidyl peptidases are exopeptidases responsible for proteolytic transformations, specifically cleaving the peptide bond after the penultimate proline residue. DPP4 is a serine protease displaying a critical role in cell adhesion, inflammation processes and immune regulation by deactivating GLP-1 and hence lowering blood glucose levels [146]. Type 2 diabetes is the main therapeutic area were DPP4 ligands have been discovered (Figures 10 and 11, Table 3).   [138]. Branched sulfamides integrating the 1-phenyl-2-phenethylamine scaffold, elaborated by Akıncıoğlu et al. [139] were found to be single-digit nanomolar inhibitors of both type I/II hCA (Figure 8c).

Dipeptidyl Peptidases (DPP)
Dipeptidyl peptidases are exopeptidases responsible for proteolytic transformations, specifically cleaving the peptide bond after the penultimate proline residue. DPP4 is a serine protease displaying a critical role in cell adhesion, inflammation processes and immune regulation by deactivating GLP-1 and hence lowering blood glucose levels [146]. Type 2 diabetes is the main therapeutic area were DPP4 ligands have been discovered (Figures 10 and 11, Table 3). More advanced DBH inhibitors are constituted by imidazolethione amines, such as etamicastat [142,143], nepicastat [144] or zamicastat [145], with low resemblance to dopaminergic amines.

Dipeptidyl Peptidases (DPP)
Dipeptidyl peptidases are exopeptidases responsible for proteolytic transformations, specifically cleaving the peptide bond after the penultimate proline residue. DPP4 is a serine protease displaying a critical role in cell adhesion, inflammation processes and immune regulation by deactivating GLP-1 and hence lowering blood glucose levels [146]. Type 2 diabetes is the main therapeutic area were DPP4 ligands have been discovered (Figures 10 and 11, Table 3).   [154] and and Pei et al. [155] developed pyrrolidine-constrained and piperidine-constrained phenethylamines selectively targeting DPP4 with interesting PK profiles ( Figure 11).

Dopamine Receptors (DX)
Dopamine receptors are a class of GPCR widely distributed in the brain, with key functionalities related to cognition, motivation and muscular drive. Pharmacologically, they are grouped into two families: D1-type (D1 and D5 receptors) and D2-type (D2S, D2L, D3 and D4) [156,157]. Medicinal chemistry of D1/D2-type receptor ligands addresses mainly the treatment of schizophrenia. From the chemical point of view concerning this review, a few small molecules presenting a basic 2-phenethylamine structure are reported in the literature ( Figure 12, Table 4).     [154] and and Pei et al. [155] developed pyrrolidine-constrained and piperidine-constrained phenethylamines selectively targeting DPP4 with interesting PK profiles ( Figure 11).

Dopamine Receptors (DX)
Dopamine receptors are a class of GPCR widely distributed in the brain, with key functionalities related to cognition, motivation and muscular drive. Pharmacologically, they are grouped into two families: D1-type (D1 and D5 receptors) and D2-type (D2S, D2L, D3 and D4) [156,157]. Medicinal chemistry of D1/D2-type receptor ligands addresses mainly the treatment of schizophrenia. From the chemical point of view concerning this review, a few small molecules presenting a basic 2-phenethylamine structure are reported in the literature ( Figure 12, Table 4).   Sitagliptin DPP4 [152,153] Backes et al. [154] and and Pei et al. [155] developed pyrrolidine-constrained and piperidine-constrained phenethylamines selectively targeting DPP4 with interesting PK profiles ( Figure 11).

Dopamine Receptors (DX)
Dopamine receptors are a class of GPCR widely distributed in the brain, with key functionalities related to cognition, motivation and muscular drive. Pharmacologically, they are grouped into two families: D1-type (D1 and D5 receptors) and D2-type (D2S, D2L, D3 and D4) [156,157]. Medicinal chemistry of D1/D2-type receptor ligands addresses mainly the treatment of schizophrenia. From the chemical point of view concerning this review, a few small molecules presenting a basic 2-phenethylamine structure are reported in the literature ( Figure 12, Table 4).

Dopamine Transporter (DAT)
The dopamine transporter receptor modulates the availability of released dopamine in the synaptic space by relocating it back into the presynaptic cell. It serves as a main target for recreational drugs as well as psychostimulant and antidepressant drugs. Classically, DAT ligands are classified in amphetamine-type and cocaine-type structures [164]. While cocaine-type molecules exert inhibitory binding to DAT, amphetamine-type ones are substrates that are effectively transported to the presynaptic neuron, stimulating efflux of cytosolic dopamine [165].
Amphetamine-type DAT ligands can be grouped in two families: amphetamine derivatives 107 and cathinone derivatives 114. Amphetamines are 1-alkyl-2-phenethylamine derivatives 107 summarized below ( Figure 13, Table 5). SAR attributes [166] are well known in this series, with diversification of the biological response with aryl substitutions, pharmacokinetic parameter shift upon alkylation of the amino group and decrease in dopaminergic pathways influenced by elongation of the alkyl chain at position 1. Due to being controlled substances in most countries, the number of compounds is constantly increasing, trying to avoid the introduction of compounds in the corresponding prohibition lists of each state [164,167]. Major concerns of this series are neurotoxicity, myocardial infarction, aneurysms, pulmonary hypertension, and tooth decay [168].

Dopamine Transporter (DAT)
The dopamine transporter receptor modulates the availability of released dopamine in the synaptic space by relocating it back into the presynaptic cell. It serves as a main target for recreational drugs as well as psychostimulant and antidepressant drugs. Classically, DAT ligands are classified in amphetamine-type and cocaine-type structures [164]. While cocaine-type molecules exert inhibitory binding to DAT, amphetamine-type ones are substrates that are effectively transported to the presynaptic neuron, stimulating efflux of cytosolic dopamine [165].
Amphetamine-type DAT ligands can be grouped in two families: amphetamine derivatives 107 and cathinone derivatives 114. Amphetamines are 1-alkyl-2-phenethylamine derivatives 107 summarized below ( Figure 13, Table 5). SAR attributes [166] are well known in this series, with diversification of the biological response with aryl substitutions, pharmacokinetic parameter shift upon alkylation of the amino group and decrease in dopaminergic pathways influenced by elongation of the alkyl chain at position 1. Due to being controlled substances in most countries, the number of compounds is constantly increasing, trying to avoid the introduction of compounds in the corresponding prohibition lists of each state [164,167]. Major concerns of this series are neurotoxicity, myocardial infarction, aneurysms, pulmonary hypertension, and tooth decay [168].

HIV-1 Reverse Transcriptase Receptor
Human immunodeficiency virus (HIV), origin of acquired immunodeficiency syndrome (AIDS), is a single-stranded (ss) RNA virus whose infection and propagation mechanisms requires reverse transcription into double-stranded (ds) DNA as a critical stage [173]. HIV-1 reverse transcriptase receptor (HIV-1 RT) is a well-explored target for antiretroviral therapies [174].  Figure 13. Amphetamine/cathinone-type families.

HIV-1 Reverse Transcriptase Receptor
Human immunodeficiency virus (HIV), origin of acquired immunodeficiency syndrome (AIDS), is a single-stranded (ss) RNA virus whose infection and propagation mechanisms requires reverse transcription into double-stranded (ds) DNA as a critical stage [173]. HIV-1 reverse transcriptase receptor (HIV-1 RT) is a well-explored target for antiretroviral therapies [174].

HIV-1 Reverse Transcriptase Receptor
Human immunodeficiency virus (HIV), origin of acquired immunodeficiency syndrome (AIDS), is a single-stranded (ss) RNA virus whose infection and propagation mechanisms requires reverse transcription into double-stranded (ds) DNA as a critical stage [173]. HIV-1 reverse transcriptase receptor (HIV-1 RT) is a well-explored target for antiretroviral therapies [174].
primary amine into a secondary one was associated with a prominent loss in 5-HT2A activity. N-benzyl substitution was found to be the exception, increasing affinity and potency at the receptor [196]. SAR exploration of the NBOMes scaffold led to defining avoidable regions for SAR expansion, while mapping tolerated substitutions seeking potency/selectivity [197]. From the original 25X-NBOMe halide derivatives [198], different derivatives have evolved.
Jensen et al. developed 25CN-NBOH (135) (Figure 17a) as a result of halide substitution by the cyano moiety, displaying high-picomolar/low-nanomolar binding affinities (competition binding assays with [ 3 H]ketanserin) and functional potencies at 5-HT2A receptor. Leth-Petersen et al. [199] designed a library of 25B-NBOMe analogues 136, such as 137 or 138 in the search of decreasing intrinsic clearance (Figure 17b). Despite the authors' efforts to decrease intrinsic clearance by lipophilicity reduction, no correlation was found, although several 5-HT2 potent compounds were synthesized. Nichols et al. [200] explored the impact of methoxy and bromo scanning along the benzyl ring of 25I-NBOMe (139). Ortho or meta positions enhanced activity, whereas the para substitution reduced it. One of the best derivatives was 140, which was compared with its tryptamine congener 141, less potent overall in the 5-HT2 assays performed (Figure 17c). NBOMes and polyalkoxylated phenethylamines could be envisaged as mescaline (Figure 16, 142) evolving structures. In this sense, significant efforts have been made to derive rational SAR maps together with attractive bioactive chemical matter [201]. Marcher-Rørsted et al. [202] reported the insertion of 2,5-dimethoxy motif in phenethylamine-like 5-HT2A agonists. They demonstrated that this motif is relevant for in vivo potency, but without observed correlations in affinity or potency in competition binding assays (Figure 18a). Oxygen-to-sulfur exchange reduces hallucinogenic-associated activity [203], while removal of one of the 2-or 5-position methoxy groups decreased in vivo activity [166]. Porter et al. [204] have derived 3-amino-chromanes and tetrahydroquinolines as selective 5-HT2B/5-HT7 ligands (Figure 18b). 5-HT2B is not considered an optimal target,  (Figure 17a) as a result of halide substitution by the cyano moiety, displaying high-picomolar/low-nanomolar binding affinities (competition binding assays with [ 3 H]ketanserin) and functional potencies at 5-HT 2A receptor. Leth-Petersen et al. [199] designed a library of 25B-NBOMe analogues 136, such as 137 or 138 in the search of decreasing intrinsic clearance (Figure 17b). Despite the authors' efforts to decrease intrinsic clearance by lipophilicity reduction, no correlation was found, although several 5-HT 2 potent compounds were synthesized. Nichols et al. [200] explored the impact of methoxy and bromo scanning along the benzyl ring of 25I-NBOMe (139). Ortho or meta positions enhanced activity, whereas the para substitution reduced it. One of the best derivatives was 140, which was compared with its tryptamine congener 141, less potent overall in the 5-HT 2 assays performed (Figure 17c).
NBOMes and polyalkoxylated phenethylamines could be envisaged as mescaline (Figure 16, 142) evolving structures. In this sense, significant efforts have been made to derive rational SAR maps together with attractive bioactive chemical matter [201]. Marcher-Rørsted et al. [202] reported the insertion of 2,5-dimethoxy motif in phenethylamine-like 5-HT 2A agonists. They demonstrated that this motif is relevant for in vivo potency, but without observed correlations in affinity or potency in competition binding assays (Figure 18a).
Oxygen-to-sulfur exchange reduces hallucinogenic-associated activity [203], while removal of one of the 2-or 5-position methoxy groups decreased in vivo activity [166]. Porter et al. [204] have derived 3-amino-chromanes and tetrahydroquinolines as selective 5-HT 2B / 5-HT 7 ligands (Figure 18b). 5-HT 2B is not considered an optimal target, due to valvular heart disease and myofibroblast proliferation by long-term consumption of selective agonists [205,206]. 5-HT 7 is implicated in sleep, mood and circadian rhythm functions [207]. Kolaczynska et al. [208] analyzed the impact in 5-HT activity of 4-alkoxy exploration of 2,5dimethoxyphenethylamines and amphetamines (Figure 18c). Both derivatives were found to interact strongly and selectively with 5-HT 2A , demonstrating that size and lipophilicity increase in this region favors 5-HT 2A/C affinity. Schultz et al. [209] and Nichols et al. [210] explored the fusion of furane/pyrane rings with the aromatic ring, as probes of the binding pocket size of 5-HT 2A receptor subtype and lone pair suitable orientation of the 2,5-oxy substituents, furnishing nanomolar-range receptor affinities (Figure 18d). McLean et al. [211] portrayed the conformationally restriction of 2-phenethylamines via 1-aminomethylbenzo cycloalkanes syntheses (Figure 18e). Benzocyclobutene derivative 153's strong potency against 5-HT 2A showed the hypothesis that the side chain of the phenethylamine binds in an out-of-the-plane conformation. Some of these conformationally restricted phenethylamines exhibit affinity for muscarinic receptors [212]. due to valvular heart disease and myofibroblast proliferation by long-term consumption of selective agonists [205,206]. 5-HT7 is implicated in sleep, mood and circadian rhythm functions [207]. Kolaczynska et al. [208] analyzed the impact in 5-HT activity of 4-alkoxy exploration of 2,5-dimethoxyphenethylamines and amphetamines (Figure 18c). Both derivatives were found to interact strongly and selectively with 5-HT2A, demonstrating that size and lipophilicity increase in this region favors 5-HT2A/C affinity. Schultz et al. [209] and Nichols et al. [210] explored the fusion of furane/pyrane rings with the aromatic ring, as probes of the binding pocket size of 5-HT2A receptor subtype and lone pair suitable orientation of the 2,5-oxy substituents, furnishing nanomolar-range receptor affinities (Figure 18d). McLean et al. [211] portrayed the conformationally restriction of 2-phenethylamines via 1-aminomethylbenzocycloalkanes syntheses (Figure 18e). Benzocyclobutene derivative 153's strong potency against 5-HT2A showed the hypothesis that the side chain of the phenethylamine binds in an out-of-the-plane conformation. Some of these conformationally restricted phenethylamines exhibit affinity for muscarinic receptors [212].

Monoamine Oxidase (MAO) Receptors
Monoamine oxidases (MAO) are flavin-containing enzymes that catalyze the oxidative deamination of monoamines, which are bound to the outer membrane of mitochondria.

Monoamine Oxidase (MAO) Receptors
Monoamine oxidases (MAO) are flavin-containing enzymes that catalyze the oxidative deamination of monoamines, which are bound to the outer membrane of mitochondria. Common MAO substrates are 5-hydroxy-tryptamine and catecholamines (dopamine, norepinephrine and epinephrine). MAO A and MAO B are the two enzyme isoforms, sharing a 70% sequence identity and differentiating each other in the substrate scope [213]. Theoretical approaches to rationalize isoform selection by substrates have been described [214,215]. As these two oxidases are responsible for neurotransmitter inactivation by oxidation, their dysfunction drives several neurological disorders, hence the therapeutic attractiveness ( Figure 19, Table 7). isoforms, sharing a 70% sequence identity and differentiating each other in the substrate scope [213]. Theoretical approaches to rationalize isoform selection by substrates have been described [214,215]. As these two oxidases are responsible for neurotransmitter inactivation by oxidation, their dysfunction drives several neurological disorders, hence the therapeutic attractiveness ( Figure 19, Table 7).

Opioid Receptors
Opioid receptors are a class of GPCR proteins consisting of three receptor types, mainly µ-, δ-, and κ-types, with a variety of functional roles in the nervous system, such as pain signaling, growth, respiration, and immunological response [223,224]. Opioid ligands modulate neuronal inhibition and ultimately analgesia. Relevant side effects are well known, such as constipation or drug dependence/abuse.

Opioid Receptors
Opioid receptors are a class of GPCR proteins consisting of three receptor types, mainly µ-, δ-, and κ-types, with a variety of functional roles in the nervous system, such as pain signaling, growth, respiration, and immunological response [223,224]. Opioid ligands modulate neuronal inhibition and ultimately analgesia. Relevant side effects are well known, such as constipation or drug dependence/abuse.

Peroxisome Proliferator-Activated (PPAR) Receptors
Peroxisome proliferator-activated (PPAR) receptors are peroxisome receptors and subcellular organelles performing several tasks related to cholesterol and fatty acid metabolism. Three members, named PPAR-α, PPAR-δ, and PPAR-γ, form this family, with different levels of expression and functionalities in diverse tissues, from energy storage in endothelial and vascular smooth muscle cells (type γ) to energy expenditure across all bodies (type δ). Several agents have been developed in relation to PPAR to address obesity, inflammation or neurodegenerative disorders ( Figure 21, Table 8) [233,234].

Peroxisome Proliferator-Activated (PPAR) Receptors
Peroxisome proliferator-activated (PPAR) receptors are peroxisome receptors and subcellular organelles performing several tasks related to cholesterol and fatty acid metabolism. Three members, named PPAR-α, PPAR-δ, and PPAR-γ, form this family, with different levels of expression and functionalities in diverse tissues, from energy storage in endothelial and vascular smooth muscle cells (type γ) to energy expenditure across all bodies (type δ). Several agents have been developed in relation to PPAR to address obesity, inflammation or neurodegenerative disorders ( Figure 21, Table 8) [233,234].

Peroxisome Proliferator-Activated (PPAR) Receptors
Peroxisome proliferator-activated (PPAR) receptors are peroxisome receptors and subcellular organelles performing several tasks related to cholesterol and fatty acid metabolism. Three members, named PPAR-α, PPAR-δ, and PPAR-γ, form this family, with different levels of expression and functionalities in diverse tissues, from energy storage in endothelial and vascular smooth muscle cells (type γ) to energy expenditure across all bodies (type δ). Several agents have been developed in relation to PPAR to address obesity, inflammation or neurodegenerative disorders ( Figure 21, Table 8) [233,234].

Sigma Receptors
Initially described as opioid receptors, sigma receptors conform their own family, unrelated to other receptors. Both members σ1R and σ2R are primarily found at the endoplasmic reticulum, and participate in diverse conditions, such as cancer, pain, neurodegenerative diseases or depression [243]. BD-1047 ( Figure 22) is an open-chain, flexible 2phenethylamine acting as antagonist of σ1R [244].

Sigma Receptors
Initially described as opioid receptors, sigma receptors conform their own family, unrelated to other receptors. Both members σ1R and σ2R are primarily found at the endoplasmic reticulum, and participate in diverse conditions, such as cancer, pain, neurodegenerative diseases or depression [243]. BD-1047 ( Figure 22) is an open-chain, flexible 2-phenethylamine acting as antagonist of σ1R [244].

Trace Amine-Associated Receptors (TAAR)
Relatively recently discovered, trace amine-associated receptors (TAAR) are a GPCR family composed of nine members (TAAR1 to 9) with prospective therapeutic applications in the field of schizophrenia and metabolic disorders [245]. Lewin et al. [246] carried out SAR explorations with simple 2-phenethylamines to envisage improved pharmacological hits ( Figure 23).

Methods
All described compounds, targets and activities were retrieved using "2-phenethylamine" as title or keyword term in the chemical databases SciFinder [247] and Scopus [248]. Additionally, a SciFinder and Scopus structure search, with the scope described early in this review (Figure 2), was employed.

Conclusions
This review represents a concise, central summary of relevant 2-phenethylaminebased leads and research hits, which spans receptors and their corresponding therapeutic indications. This report serves as a guide to researchers interested in medicinal chemistry to identify suitable ligand-target associations displaying the aforementioned motif, as well as help to identify prospective targets of brand-new molecules with the 2-phenethylamine core embedded.
Future directions will include both a complementary report covering synthetic strategies to access 2-phenethylamine derivatives and a second, satellite review of 2-heteroaryl-ethylamines in medicinal chemistry.

Trace Amine-Associated Receptors (TAAR)
Relatively recently discovered, trace amine-associated receptors (TAAR) are a GPCR family composed of nine members (TAAR1 to 9) with prospective therapeutic applications in the field of schizophrenia and metabolic disorders [245]. Lewin et al. [246] carried out SAR explorations with simple 2-phenethylamines to envisage improved pharmacological hits ( Figure 23).

Sigma Receptors
Initially described as opioid receptors, sigma receptors conform their own family, unrelated to other receptors. Both members σ1R and σ2R are primarily found at the endoplasmic reticulum, and participate in diverse conditions, such as cancer, pain, neurodegenerative diseases or depression [243]. BD-1047 ( Figure 22) is an open-chain, flexible 2-phenethylamine acting as antagonist of σ1R [244].

Trace Amine-Associated Receptors (TAAR)
Relatively recently discovered, trace amine-associated receptors (TAAR) are a GPCR family composed of nine members (TAAR1 to 9) with prospective therapeutic applications in the field of schizophrenia and metabolic disorders [245]. Lewin et al. [246] carried out SAR explorations with simple 2-phenethylamines to envisage improved pharmacological hits ( Figure 23).

Methods
All described compounds, targets and activities were retrieved using "2-phenethylamine" as title or keyword term in the chemical databases SciFinder [247] and Scopus [248]. Additionally, a SciFinder and Scopus structure search, with the scope described early in this review (Figure 2), was employed.

Conclusions
This review represents a concise, central summary of relevant 2-phenethylaminebased leads and research hits, which spans receptors and their corresponding therapeutic indications. This report serves as a guide to researchers interested in medicinal chemistry to identify suitable ligand-target associations displaying the aforementioned motif, as well as help to identify prospective targets of brand-new molecules with the 2-phenethylamine core embedded.
Future directions will include both a complementary report covering synthetic strategies to access 2-phenethylamine derivatives and a second, satellite review of 2-heteroaryl-ethylamines in medicinal chemistry.

Methods
All described compounds, targets and activities were retrieved using "2-phenethylamine" as title or keyword term in the chemical databases SciFinder [247] and Scopus [248]. Additionally, a SciFinder and Scopus structure search, with the scope described early in this review (Figure 2), was employed.

Conclusions
This review represents a concise, central summary of relevant 2-phenethylamine-based leads and research hits, which spans receptors and their corresponding therapeutic indications. This report serves as a guide to researchers interested in medicinal chemistry to identify suitable ligand-target associations displaying the aforementioned motif, as well as help to identify prospective targets of brand-new molecules with the 2-phenethylamine core embedded.
Future directions will include both a complementary report covering synthetic strategies to access 2-phenethylamine derivatives and a second, satellite review of 2-heteroarylethylamines in medicinal chemistry. Funding: The authors gratefully acknowledge the financial support of this work provided by Ministerio de Ciencia e Innovación (PID2020-118303GB-I00/MCIN/AEI/10.13039/501100011033) and Junta de Castilla y Leon (SA0076P20). C.T.N. thanks Junta de Castilla y Leon for a postdoctoral contract (SA0076P20).