5-HT1A receptor is one of the most important members of the numerous families of serotoninergic receptors. Though it was the first 5-HT receptor to be identified and cloned, the knowledge of its activation/transduction mechanisms, mediated effects, and connection with other systems is still uncompleted. For this reason, relevant is the study of the four Ws of the title: first of all “who” this receptor is, then “why” it continues to be a so attractive target after several years after its identification, then “where” is 5-HT1A receptor expressed within the body, and, finally, “what” effects this receptor can elicit under physiological and pathological conditions. Obviously, more and more potent, safe, and selective “drugs” might be discovered once the responses to these questions are given.
- 5-HT1A receptor
- 5-HT1A transduction mechanisms
- central nervous system diseases
- 5-HT1A ligands
- structure-activity relationship studies
The rational research of novel efficacious and safe drugs is mainly based on the knowledge of biological systems, whose dysfunctions cause several pathological conditions. Receptors and enzymes are the most common targets to which the so-called charmed bullets by Paul Ehrlich (1854–1915), Nobel Prize in Physiology and Medicine in 1908, should be addressed to mean the selectivity of interaction and, therefore, the reduced occurrence of unwanted side effects. Serotonin receptors (5-HTRs) are the most widespread targets of drugs because of the numerous biological effects of the endogenous ligand serotonin (5-HT; Figure 1) and the wide presence of different 5-HTR subtypes in both the central and peripheral nervous systems (CNS and PNS) .
5-HT is biosynthesized at the periphery into the gut by intestinal enterochromaffin cells and in the CNS in the raphe nucleus from the essential amino acid L-tryptophan. A 5-HT reuptake protein (SERT) is responsible for carrying the neurotransmitter from the synaptic cleft to its target nerve and acts as a regulator of 5-HT levels. In the CNS, SERT is a key target for various antidepressant drugs such as tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and serotonin-norepinephrine reuptake inhibitors (SNRIs). 5-HT is mainly deaminated by monoamine oxidase A (MAO A) to the corresponding aldehyde in the liver. The physiological effects of 5-HT are mediated by several 5-HTRs, whose heterogeneity was hypothesized from pharmacological characterization in the 1950s. From radioligand experiments, the first evidences of 5-HT subtypes were reported in 1979 . To date molecular cloning techniques, amino acid sequence determination, evaluation of its pharmacological properties, second messenger coupling, and signal transduction characterization have allowed the identification of at least seven subfamilies (5-HT1–7), some of which are further subdivided into different subtypes (Figure 2).
While 5-HT3Rs are cation-permeable ion channels, all the others are G-protein-coupled receptors (GPCRs) and are classified as rhodopsine-like receptors (class A). Among the 5-HTRs, the 5-HT1A subtype was the first to be cloned  and pharmacologically characterized, and it is one of the most studied. For this reason, it is often ironically called “old target” . The human 5-HT1AR consists of 422 amino acid residues with a molecular weight of about 46,000 Da. Though its structure is still unknown, mutagenesis studies have allowed the identification of amino acid residues responsible for ligand binding and G-protein coupling .
5-HT1ARs are widely expressed in the brain of mammals, including humans . The main expressions are in limbic areas, such as the hippocampus, lateral septum, cortical brain regions, as well as dorsal and medial raphe nuclei (DRN and MRN) (Figure 3).
5-HT1ARs are located within the brain both pre- and postsynaptically. Presynaptic 5-HT1ARs are expressed in all 5-HT neurons (autoreceptors) and in a lot of non-5-HT neurons (heteroreceptors). The latter modulate the release of several neurotransmitters, including glutamate and dopamine, and hormones (adrenocorticotropin (ACHT), oxytocin, prolactin, growth hormone, β-endorphin). In the brainstem, presynaptic autoreceptors are expressed in serotonergic neurons in DRN and MRN, where their activation inhibits cell firing rate. These neurons send ascending 5-HT fibers to the forebrain attenuating 5-HT synthesis, turnover, and release in projection areas from axon terminals, working on a basis of a negative feedback. Presynaptic 5-HT1ARs expressed in DRN, through coupling to Gαi/o proteins, decrease rate of cell firing by the activation of inwardly rectifying potassium channels. Postsynaptic 5-HT1ARs are found at high density in limbic regions, such as the hippocampus and septum, and in the frontal and entorhinal cortices. Lower 5-HT1AR levels are observed in the amygdala. As in the case of presynaptic receptors, the activation of postsynaptic 5-HT1ARs generally decreases the firing rate of postsynaptic cells. Electrophysiological, pharmacological, and biochemical evidences have demonstrated that 5-HT1ARs are localized in primary afferent neurons . They are also present in the gut, in the enteric nervous system, as well as in smooth muscle, where their activation inhibits relaxation or contraction.
3. Signal transduction pathways of 5-HT1ARs
The primary transduction pathway of 5-HT1ARs is the inhibition of adenylate cyclase (AC). Nevertheless, various other pathways are coupled to this receptor depending on the target cell. Indeed, 5-HT1AR stimulation activates or inhibits different enzymes, channels, and kinases, as well as modulates the production of several second messengers (Figure 4) [6, 7].
Whatever is the activated second messenger, the signals initiated by the stimulation of 5-HT1ARs implicate the involvement of Gi/o protein. Moreover, a G-protein-independent pathway of 5-HT1AR coupling to a smooth inward current has also been suggested.
3.1. AC inhibition
The activation of 5-HT1ARs inhibits AC and reduces the production of cAMP with a consequent decrease of protein kinase A (PKA) activity. The Gαi-induced inhibition of AC is coupled to 5-HT1A heteroreceptors, whereas the situation is still unclear for 5-HT1A autoreceptors. Indeed, some results reveal that 5-HT1AR partial agonists negatively regulate presynaptic AC activity in raphe nuclei. On the other hand, a lot of evidences highlight that 5-HT1AR agonists do not inhibit forskolin-stimulated AC activity in homogenates of the raphe region, suggesting that these autoreceptors do not couple to AC. 5-HT1AR agonists also reduce PKA activity in the hippocampus, determining increased protein phosphatase-1 activity and reduction of Calcium/calmodulin-dependent protein kinase II phosphorylation. This signaling effect is joined to cognitive deficits. Therefore, cognitive behaviors can be mediated by the inhibition of AC/PKA activity induced by 5-HT1ARs.
3.2. GIRK and Ca2+ channel opening
Through coupling to Gαi/o proteins, 5-HT1ARs activate inwardly rectifying potassium channels (GIRKs) in the hippocampus and DRN. Such an action hyperpolarizes neurons and decreases firing. Moreover, Ca2+ entry is reduced by the inhibition of voltage-gated Ca2+ channel following 5-HT1AR activation.
3.3. ERK/MAPK pathway activation
The stimulation of 5-HT1ARs induces the release of βγ-complex that participates in the activation of phosphatidylinositol-3 kinase (PI3K). It triggers the activation of extracellular signal-regulated protein kinase (ERK) (or MAPK), implicated in cell proliferation and differentiation through two pathways involving Ras-Raf-MEK proteins. In addition, 5-HT1A-induced ERK activation in nonneuronal cells can be mediated by phosphatidylcholine-specific phospholipase C (PC-PLC) in a G-protein-dependent manner. In neuronal cells, the effects on ERK activity produced by 5-HT1ARs can be different. Indeed, in the hypothalamus a rapid but transient increase of ERK phosphorylation is observed, and this effect might be an intermediate step for the 5-HT1AR-mediated increase of oxytocin, ACTH, and prolactin. In HN2-5 hippocampal-derived cell lines, 5-HT1AR activation favors ERK phosphorylation and activity. This effect does not occur in the primary culture of hippocampal or fetal rhombencephalic neurons. On the contrary, in the rat hippocampus, 5-HT1AR activation decreases ERK phosphorylation. Analogously it reduces MEK activity and ERK phosphorylation in differentiated raphe neurons. Different ERK-related effectors can be modulated by 5-HT1ARs: activation of the ribosomal S6 kinase (RSK), stimulation of nuclear factor κB (NF-κB), and inhibition of caspase 3. This pathway seems to be involved in neuroprotective mechanisms. ERK also activates cAMP response element binding (CREB), a transcription factor that plays fundamental roles in stress, anxiety, and depression. Finally, the activation of MAPK/ERK transduction pathway may inhibit apoptosis by phosphorylation of the proapoptotic protein Bad and by increasing the expression of antiapoptotic Bcl-2.
3.4. PI3K and Akt pathway activation
5-HT1AR stimulation can also regulate the activation of the PI3K/Akt signaling pathway through βγ-complex. The Akt protein kinase plays a key role in several cellular processes, such as glucose metabolism, apoptosis, cell proliferation, transcription, and cell migration. In the mammalian brain, the PI3K/Akt pathway is also implicated in synaptic plasticity, learning, and memory. Consequently, Akt dysfunction can be associated with metabolic diseases (e.g., diabetes and obesity), central disorders (e.g., depression, schizophrenia, and drug abuse), and the most frequent alterations observed in human cancer and tumor cells. Akt phosphorylates and inactivates the protein glycogen synthase kinase 3 (GSK3), whose inhibition produces antidepressant and antimanic effects. Active Akt also phosphorylates and inactivates Forkhead box O (FoxO) transcription factors, whose deficiency in mice develops antidepressive and anxiolytic behavioral phenotypes.
3.5. Na+/H+ exchanger activation
Another complex pathway following 5-HT1AR stimulation and involving G(i2)α and/or G(i3)α induces Janus kinase 2 (Jak2) activation, which leads to tyrosine phosphorylation of calmodulin (CaM). The consequent increase of CaM binding to Na+/H+ exchangers (NHEs) induces a conformational modification that activates NHEs, unmasking an obscured proton-sensing and/or proton-transporting region. NHEs, expressed on the surface of all mammalian cells, regulate cell volume, intracellular pH, and transepithelial transport of Na+ and acid-base equivalents.
3.6. NO production
5-HT1ARs can also regulate the production of nitric oxide (NO) that plays an important role in the brain. In rat ventral prostate cells, 5-HT1ARs can stimulate NO synthase (NOS) activity, whereas in the adult rat hippocampus and in human neocortical slices, they inhibit NMDA-induced NO production. Therefore, the regulation of NO synthesis by 5-HT1ARs is complex and appears to be cell specific.
4. Biological interest of 5-HT1ARs
5-HT1AR is one of the most important among the 5-HTRs because of its high affinity for 5-HT and involvement in nearly all 5-HT-mediated effects. The main behavioral and physiological functions mediated by this receptor are summarized in Figure 5.
The dysfunction of 5-HT1A autoreceptors has been proven to be associated with the major depressive disorders. This correlation is confirmed by the observation that significant antidepressant activity is elicited by 5-HT1AR agonists . Though the mechanism responsible for their antidepressant action is still unclear, desensitization or downregulation of presynaptic 5-HT1ARs appears to be implicated in this pharmacological effect. Indeed, in DRN and MRN, prolonged treatment with 5-HT1AR agonists desensitizes presynaptic 5-HT1ARs inducing a reduction of autoreceptor-mediated inhibition of 5-HT release.
SSRIs represent the first-line treatment of depression. However, the inhibition of the reuptake of 5-HT increases 5-HT concentration in the synaptic cleft and simultaneously activates 5-HT1A autoreceptors, with a consequent suppression of 5-HT release from presynaptic terminals . Therefore, only prolonged treatment with SSRIs allows the desensitization of 5-HT1A autoreceptors, leading to the recovery of neurotransmission in 5-HT neurons. Beneficial effects on depression are also produced by the combination of SSRIs with 5-HT1AR agonists or antagonists, leading to faster onset of antidepressant action and greater antidepressant efficacy. In particular, 5-HT1AR antagonists can improve the efficacy of SSRIs by blocking inhibitory 5-HT1A autoreceptors, while 5-HT1AR agonists exert antidepressant-like effect through the activation of postsynaptic 5-HT1ARs and/or faster desensitization of 5-HT1A autoreceptors. Finally, antidepressant-like effect can also be produced by 5-HT1A partial agonism combined with 5-HT reuptake inhibition .
Several studies have been performed to demonstrate the possible role of 5-HT1ARs in anxiety . Interestingly, mice with genetically inactivated 5-HT1AR gene develop an anxiety-like phenotype, probably resulting from impaired autoinhibitory control of midbrain 5-HT neurons. On the contrary, mice with overexpressed 5-HT1ARs display diminished anxiety when compared to wild-type animals. These findings support the crucial role of the stimulation of 5-HT1ARs in the control of anxiety-like behavior. Therefore, 5-HT1AR agonists and partial agonists have been developed as novel anxiolytic agents, devoid of dependence and side effect profile of other anxiolytics and antipsychotics.
Several studies performed in postmortem schizophrenia patients report an overexpression of 5-HT1ARs in the prefrontal cortex, indicating that these receptors are not adequately stimulated by 5-HT . Therefore, 5-HT1AR agonists might be useful to contrast this apparent deficit. Two mechanisms are advantageously activated by 5-HT1AR stimulation in the treatment of schizophrenia. The first one involves the attenuation of parkinsonian symptoms, such as catalepsy, caused by the antagonism at dopamine D2 receptor (D2R) produced by antipsychotics. Since atypical antipsychotic drugs, such as clozapine, quetiapine, and ziprasidone, also behave as potent 5-HT1AR agonists, it has been suggested that the reduced incidence of motor side effects observed with these drugs might be due to their inherent 5-HT1AR agonism. The second mechanism involves the ability of 5-HT1AR agonists to increase dopamine release in the prefrontal cortex, consequently reducing the negative symptoms of schizophrenia. Based on these observations, a novel approach in the treatment of schizophrenia concerns the development of novel atypical antipsychotic agents characterized by a mixed D2R antagonist/5-HT1AR agonist profile.
Full and partial 5-HT1AR agonists are beneficial in pain treatments, including efficacy in neuropathic pain models, arousing great interest as future therapeutic agents. In knockout mice, 5-HT1ARs have also been demonstrated to mediate an endogenous inhibitory control of nociception evoked by thermal noxious stimuli .
4.5. Drug addiction
A critical role in the effects of psychostimulants, including addiction, is played by 5-HT1ARs. Some psychostimulant drugs, including cocaine, amphetamine, methamphetamine, and 3,4-methylenedioxymethamphetamine (MDMA), increase not only dopamine but also 5-HT that can hyperactivate 5-HT1ARs. Interestingly, the contribution of pre- and postsynaptic 5-HT1ARs can be dissociated and frequently is responsible for opposite effects. In fact, 5-HT1A autoreceptors indirectly facilitate psychostimulant addiction-related behaviors by reducing 5-HT response in projection terminal areas, while postsynaptic 5-HT1ARs directly contrast the expression of various addiction-related behaviors . Several studies have also demonstrated that 5-HT1AR agonists alleviate opioid-induced respiratory depression in rodent models. The mechanisms involved in this effect are still unclear. However, concomitant decreases in opioid-induced analgesia, as well as altered baseline ventilation and behavior, have also been observed.
5-HT1ARs are involved in the regulation of locomotor activity. In particular, the stimulation of 5-HT1ARs facilitates the establishment of locomotor sensitization . Parkinsonian patients in therapy with L-3,4-dihydroxyphenylalanine (L-DOPA) may develop motor complications, such as dyskinesia. The development of this side effect involves several pathways, including an abnormal 5-HT-mediated neurotransmission . It has been highlighted that parkinsonian animals chronically treated with L-DOPA have increased levels of 5-HT1ARs in the striatal matrix. Accordingly, treatment with 5-HT1AR agonists attenuates dyskinesia but, in some cases, also reduces the antiparkinsonian benefit of L-DOPA. Some evidences suggest that a lot of 5-HT1AR agonists are also endowed with D2R antagonism, which alleviates dyskinesia, though at the expense of worsening parkinsonism. The challenge is to obtain compounds able to selectively stimulate 5-HT1ARs in striatus and/or in middle layers of the cortex, avoiding the involvement of 5-HT1ARs in external cortical layers.
The activation of 5-HT1ARs exerts a neuroprotective effect in different animal models of ischemia, interfering with excitotoxic and apoptotic cell death processes in the postischemic brain . Though the cellular mechanisms underlying such a neuroprotective effect are still unclear, the hyperpolarization of pyramidal neurons inhibits the glutamate-induced excitotoxicity consequent to cerebral ischemia. 5-HT1ARs may mediate brain protective mechanisms, by contrasting the effects of glutamatergic NMDA receptor overstimulation and the consequent NMDA-induced Ca2+ influx. Moreover, the inhibition of 5-HT1AR-induced cyclases might produce neuroprotective effects due to the reduction of adenylyl cyclase excess following reperfusion after ischemic attack. 5-HT1AR agonists can also be useful for the treatment of traumatic brain injury (TBI) .
Several experimental evidences highlight that the activation of postsynaptic 5-HT1ARs, attenuating the neuronal activity, impairs emotional memory. On the contrary, presynaptic 5-HT1AR activation reduces 5-HT release and exerts pro-cognitive effects. 5-HT1AR antagonism facilitates memory retention, probably by the activation of 5-HT7Rs, and evidence is provided that 5-HT7Rs can facilitate emotional memory upon reduced 5-HT1AR transmission . Moreover, tonic and phasic 5-HT release can exert different and potentially opposite effects on emotional memory, depending on the states of 5-HT1ARs and 5-HT7Rs and their interaction. Consequently, individual differences due to genetic and/or epigenetic mechanisms play an essential role in the responsiveness to drug treatment .
4.9. Sexual function
5-HT1ARs and 5-HT2CRs produce two distinct and opposite effects on sexual function: the activation of 5-HT1ARs decreases ejaculatory latency and erection, directly promoting the sympathetic emission, while the activation of 5-HT2CRs increases them, directly favoring parasympathetic expulsion and erection . Therefore, 5-HT1AR antagonists are under investigation for the treatment of primary premature ejaculation.
4.10. Cardiovascular system
Several studies have demonstrated that 5-HT1ARs in the medullary raphe mediate protective responses to stress . Indeed, the activation of 5-HT1ARs induces bradycardia and blood pressure decrease, suggesting that 5-HT1ARs can reduce the sympathetic outflow. Moreover, 5-HT1AR agonists reduce the cutaneous vasoconstriction evoked by physical and psychological stressors. 5-HT1ARs located in limbic regions can also reduce stress-evoked cardiovascular responses. However, this action does not occur via a direct effect on brainstem cardiovascular neurons, but is consequent to the anxiolytic effect. Psychological stress, cold exposure, or fever might elicit cardiovascular responses also mediated by neurons within the dorsomedial hypothalamus. Therefore, 5-HT1AR agonists might be useful therapeutic agents to reduce the sympathetic responses occurring in some forms of hypertension and heart failure. The cardiovascular responses of 5-HT1AR agonists could also be useful to reduce side effects in the treatment of hyperphagia and obesity with noradrenaline (NA) uptake inhibitors. Such inhibitors are able to reduce food intake due to increased noradrenergic activity that also causes an increased cardiovascular activity. When 5-HT1AR agonists are combined with NA uptake inhibitors, side effects, such as hypertension and tachycardia, are mitigated. Postsynaptic 5-HT1AR activation may contribute to hypophagia efficacy. Moreover, presynaptic 5-HT1ARs may reduce food intake by inhibiting spontaneous noradrenergic cell firing.
4.11. Urogenital system
5-HT1ARs mediate effects in the lower urinary tract function . Indeed, their stimulation activates the micturition reflex, inducing an increase in the frequency of isovolumic bladder contractions. Conversely, 5-HT1AR agonists elicit periodic external urethral sphincter relaxation, inducing an increase in micturition volume, a decrease in bladder capacity, and an increase in voiding efficiency.
4.12. Pupillary dilation
Pupillary response to 5-HT1AR agonists is species dependent . Indeed, 5-HT1AR activation produces miosis in humans and rabbits and mydriasis in mice. In humans, 5-HT1ARs induce miosis solely by inhibiting sympathetic mechanisms. However, evidences suggest that the parasympathetic nerve is also involved. Indeed, the activation of central 5-HT1ARs induces NA release, which in turn reduces parasympathetic neuronal tone to the iris sphincter muscle by the stimulation of postsynaptic α2-adrenoceptors (α2-ARs) within the Edinger-Westphal nucleus.
5-HT1ARs are known to be involved in the proliferation of human tumor cells, but their function still remains poorly understood . 5-HT1AR antagonists inhibit the growth of different prostatic tumor cell lines, such as PC-3, DU-145, and LNCaP, as well as the proliferation of PC-3 xenografted subcutaneously in athymic nude mice. Multitarget ligands, acting as α1A/α1D-AR and 5-HT1AR antagonists, in which a synergic effect occurs, have proved to be useful in the management of benign prostatic hyperplasia. 5-HT1ARs are also reported to be involved in the mitogenic effect of 5-HT in human small cell lung carcinoma cells.
Several structurally different ligands, such as aryloxyalkylamines, arylpiperazines, aminotetralins, indolyl-alkylamines, ergolines, and aporphines, are known to bind 5-HT1ARs . Recently, new classes of ligands, including 2-imidazoline and 1,4-dioxane derivatives, have also shown high 5-HT1AR affinity. Due to the high homology among 5-HT1ARs and other receptor systems, in binding studies several molecules show nanomolar and subnanomolar affinity not only for 5-HT1ARs but also for other receptors (5-HT2ARs, 5-HT2CRs, 5-HT7Rs, α1- and α 2-ARs, as well as D1Rs and D2Rs).
The sequence analysis of the 5-HT1AR genomic clone indicates 43% amino acid homology with the β2-AR in the transmembrane domain. Therefore, some compounds show good affinity for both systems. The first examples of dualistic interaction are offered by pindolol (
In several studies, an Asn amino acid residue in the putative helix VII of 5-HT1ARs has been demonstrated to play a crucial role in the binding of aryloxypropanolamines. Indeed, for example, propranolol
Arylpiperazines are one of the most important classes of 5-HT1AR ligands from which a second generation of anxiolytics, including buspirone (
These ligands bind with high affinity to different GPCRs; the two multitarget drugs
The general structure of arylpiperazines consists of a terminal fragment containing an amide, imide, alkyl, arylalkyl, heteroarylalkyl, or tetralin function linked through a flexible aliphatic chain of variable length to the
5.2.1. Modification of the aryl group
The replacement of the 2-pyrimidinyl moiety of
The 2-methoxyphenyl group is also present in the WAY series, including WAY 100135 (
The incorporation of the
5.2.2. Modification of the piperazine ring
The piperazine ring can be replaced by a piperidine one. The most representative example is befiradol (
A series of 2
5.2.3. Modification of the spacer
In LCPAs, the four-carbon alkyl chain seems to be the most favorable for high 5-HT1AR affinity. Indeed, its shortening reduces affinity, according to the rank order of potency C-4 > C-2 > C-3 .
However, the butyl chain can be substituted by a propylthio bridge, as confirmed by the high 5-HT1AR affinity of compound
The oxybutynin chain of aripiprazole (
The presence of a hydroxyl group in the butyl chain is well tolerated. BMY 14802 (
A hydroxyalkyl chain also characterizes a series of molecules (
In a series of compounds prepared to discover mixed 5-HT/dopamine receptor agents as novel antipsychotics, amide
The inclusion of the alkyl chain of LCAPs in a cyclohexyl ring leads to more conformationally constrained analogues (e.g.,
The alkyl chain can be partially included in aromatic functions, including pyrrole (RWJ 25730,
The insertion of the 1,3-dioxolane nucleus in the chain is also well tolerated. Compound
Similar structure-activity relationships (SARs) can be observed when the spiro-cyclohexyl terminal fragment in both piperazine and open-chain series is replaced by a 2,2-diphenyl moiety.
The replacement of the 1,3-dioxolane nucleus with other pentatomic rings bearing H-bond acceptor groups (tetrahydrofuran or cyclopentanone) or an H-bond acceptor and donor group (cyclopentanol) (Figure 22) causes an overall reduction of affinity at α1-ARs, while both potency and efficacy are increased at 5-HT1ARs.
5.2.4. Modification of the terminal fragment
The numerous structurally different terminal fragments, as already seen for ligands reported above, demonstrate that this moiety is less critical for 5-HT1AR interaction . The dual SSRI and 5-HT1AR agonist vortioxetine (
The replacement of the azaspirodecanedione moiety of
Several molecules, bearing an isonicotinic moiety as the terminal fragment of LCAPs, show nanomolar and subnanomolar affinities for 5-HT1ARs, 5-HT2ARs, and 5-HT2CRs and moderate or no affinity for other relevant receptors (D1Rs, D2Rs, α1- and α2-ARs) . In particular, derivative
, with a methylthio substituent in the ortho-position show high 5-HT1AR affinity, the replacement of the phenyl ring in the arylpiperazine moiety with a benzisoxazole system, affording, for example,
A β-tetralonohydantoin as terminal fragment characterizes a series of compounds, which show high 5-HT1AR affinity (p
Among new LNCPs with structural modifications in the terminal fragment, in the alkyl chain length and in the substituents of the piperazine fragment, the 2-ethoxy quinazolinone derivatives
In a more recent work, the quinazolinone system has been replaced by 6-phenyl-4(3
MP 3022 (
Purine 2,6-dione core has also been used as a terminal fragment to combine the 5-HT1AR activity with the phosphodiesterase (PDE) inhibition . Both effects might be advantageous in the treatment of neuropsychiatric disorders. Among the compounds bearing this core,
5.2.5. Main interactions of arylpiperazines with 5-HT1ARs
Two main interactions prove to be important for the affinity of arylpiperazines for 5-HT1ARs: (a) an ionic bond between the protonated nitrogen atom of the piperazine ring and the carboxyl oxygen of the side chain of Asp3.32 and (b) an edge-to-face CH-π interaction between the aromatic ring and the Phe6.52 residue, which stabilizes the ligand binding. The basic pharmacophore of the 5-HT1AR is the same for agonists and antagonists and consists of an aromatic nucleus and a basic nitrogen atom, whose optimal distance is 5.2 Å, while the nitrogen lies at 0.2 Å above the plane defined by the reference ring (Figure 28) .
Due to the highly flexible linker (usually 2-4 methylene units), using different experimental and modeling techniques, various attempts have been conducted to determine the bioactive conformation of LCAPs . Assuming that active conformations of LCAPs are closely related to those in solutions or in solid state, two-dimensional (2D) NMR and crystallographic methods were often applied. The 2D NMR studies indicated that compounds with tetramethylene spacer can adopt extended, bent, or folded conformations. On the other hand, analysis of Cambridge Structural Database showed that linear geometries predominated. Molecular modeling studies (conformational analysis, docking, dynamics), provided with structural investigations or conducted separately, also gave equivocal results suggesting the possibility of different bioactive conformations of LCAPs.
For a long time, 2-aminotetralin structure has been known to be pharmacologically important. Initially, aminotetralins were characterized by their sympathomimetic action, i.e., the induction of mydriasis, contraction of the uterus, changes in blood pressure, and respiration, as well as increased intestinal motility in in vivo experiments. During the late 1960s, the discovery of their activity at central dopamine receptor led to active synthesis programs all over the world. The 2-aminotetralin structure has proven to be a valuable scaffold not only for the development of 5-HTR ligands, but it also characterizes dopamine and adrenergic receptor ligands, as well as compounds interacting with melatonin receptors . The main SARs of aminotetralins are summarized in Figure 29.
The position of the hydroxyl group in the aromatic ring of the tetralin scaffold is crucial to address ligands toward 5-HT or dopamine receptors. Indeed, 8-hydroxy-2-(
Compounds obtained by replacing the 8-hydroxy substituent with 8-methoxy (8-MeO-DPAT,
Compared to the
The incorporation of the nitrogen atom in the tetralin nucleus furnishes the series of 1,2,3,4-tetrahydroisoquinoline (THIQ) derivatives, which bind to 5-HT1ARs and 5-HT2ARs. SAR studies performed on the THIQ class lead to the synthesis of 1-adamantoyloaminoalkyl derivatives endowed with high affinity for 5-HT1ARs (p
Ring contraction (indamines) or ring expansion (benzocycloheptamines) of the cycloexyl ring of 2-aminotetralins decreases 5-HT1AR affinity. The replacement of the tetralin scaffold with the chroman nucleus does not influence affinity and selectivity.
Among the four enantiomers obtained by the introduction of a methyl group in position 1 of
The restriction of the conformation of
The introduction of a methyl group in position 3 of
A different six/six fused angular tricyclic of 2-aminotetralin is obtained by incorporating the 8-oxygen atom and C-7 into a six-membered ring, obtaining
A further decrease in affinity is shown by compounds bearing an annulated pyrrole ring in which the NH moiety is in the same position as the hydroxy group of
The introduction of a formyl group at C-1 of
The prototype of this class of compounds is the endogenous ligand 5-HT (Figure 1), which behaves as a potent 5-HT1AR agonist (p
The 4-substituted tetrahydropyridine analogue of
A compound with an
The indolylalkylamine moiety is also present in multitarget compounds simultaneously acting as SSRIs and 5-HT1AR antagonists and potentially useful for the treatment of depression. Among these, the benzoxazine derivative
The hybridation between the chromane-based structure, present in 5-HT1AR antagonists, and the 3-indolyl-alkylamine moiety, embedded in numerous SSRIs, leads to compounds with mixed profiles. 5-Carboxamide-8-fluoro derivatives as well as 5-carboxamide-8-des-fluoro analogues with proper
The tetracyclic ergoline skeleton is a common structural element contained in all ergot alkaloids. Such compounds are used in the treatment of several pathophysiological conditions, because of their wide spectrum of central and peripheral pharmacological activities. They can be considered as rigid analogues of both indolylalkylamines and catecholamines. Therefore, it is not surprising that they are able to nonselectively bind to adrenergic, dopaminergic, and serotoninergic receptors. Potent and selective 5-HT1AR ligands have been developed by combining the structural elements of the indolylethylamines and the 2-aminotetralins into a partial ergoline skeleton . Among the compounds belonging to this series, LY228729 (
Though several tetracyclic ergolines, such as LSD (
Among the 5(10→9)
The stereochemistry at C-3 is very important for the 5-HT1AR profile. In particular, compound
These compounds, whose prototype is (
The observation that the beneficial properties of the α2C-AR agonists and α2A-AR antagonists allyphenyline (
Experiments carried out in the presence of the 5-HT1AR antagonist WAY100135 confirmed that 5-HT1AR activation is involved in the observed antidepressant-like activity . The investigation of a wide series of 2-substituted imidazolines linked to an aromatic moiety by a biatomic bridge highlighted that a polar function (-O- or –NH- group) and a methyl group in the bridge as well as the suitable chirality and a proper steric hindrance in the aromatic area favor 5-HT1AR recognition and activation. In particular, (
The design and synthesis of 5-HT1AR ligands bearing the 1,4-dioxane nucleus were inspired by the observation that the potent α1-AR antagonist WB4101 (
A good selectivity for 5-HT1ARs over α1-ARs and dopamine D2-like receptors is also obtained by inserting a –OCH2OCH3 group in 2-position of the phenoxy terminal (compound
In summary, the currently main knowledges of the four-wheel drive (4WD: who, why, where, what, and drugs) vehicle by which to travel inside the 5-HT1AR world, have been presented. Such a travel, begun 30 years ago with the identification of 5-HT1AR coding gene, is far from the conclusion. Indeed, despite no X-ray structure is deposited to date, it is possible to answer quite exhaustively the question “who” this receptor is. However, the most intriguing question is “why” it continues to be a so attractive target several years after its identification. Several evidences are available about “where” 5-HT1AR is expressed throughout the body, at both central and peripheral levels. Between presynaptic (auto- and heteroreceptors) and postsynaptic receptors, are there differences which could allow us to target them selectively? Wider and wider is the field of “what” effects this receptor can elicit under physiological and pathological conditions directly or through the modulation of several other receptor systems or the stimulation of the secretion of various hormones. Well known is its involvement in anxiety, depression, epilepsy, mood disorders, learning, and memory. Consequently, growing is its importance in the treatment of such pathologies. Moreover, the interest for 5-HT1AR as an attractive target of drugs is increased by further physiologically governed functions, including feeding/satiety, temperature regulation, sleep, pain perception, and sexual activity. The stimulation of 5-HT1ARs has been demonstrated to activate several different biochemical pathways and signals through both G-protein-dependent and G-protein-independent pathways. However, it cannot be ruled out that underlying mechanisms are far from being completely understood, making more and more complex the net of pathways through which the primary impulses unwind themselves. Finally, the discovery of “drugs” able to selectively activate or inhibit 5-HT1AR might help to better characterize such a receptor and the physiological functions in which it is involved. Despite the numerous published papers and synthesized and tested molecules, the results are not completely satisfactory yet. The reasons can be ascribed partly to the great similarity of the ligand recognition transmembrane region of 5-HT1ARs with other members of the family or other GPCRs, partly to bimodal effect of 5-HT1AR activation dependent on the neuroanatomical location of the receptors and the concentration of the ligand.