Current Medicinal Chemistry (v.19, #3)

A receptor–receptor interaction occur "when the binding of a ligand to the orthosteric or allosteric sites of one receptor causes, via directallosteric interactions, a change in the ligand recognition, decoding, and trafficking processes of another receptor". Thus, it demands theformation of receptor heterodimers or higher order heteromers, to form the so called “receptor mosaics”. In view of the likely existence ofdisease and tissue specific heteromers, novel strategies for drug treatment based on targeting the heterodimers and receptor mosaics, haverecently been introduced. Such drugs will have reduced side effects by targeting the heteromers versus the monomers and homomers.It is well known that allostery is a mode of long distance communication between distal sites in proteins. The allosteric mechanisms makepossible an integrative activity to emerge either intramolecularly in G protein-coupled receptor (GPCR) monomers or intermolecularly viareceptor–receptor interactions in GPCR homodimers, heterodimers, and receptor mosaics. In the receptor heteromers, the allostericcommunication between the two receptors takes place via the receptor interface, which therefore plays a key role in mediating the receptor–receptor interaction. The allosteric mechanisms in receptor heteromers make possible a marked rise of the repertoire of GPCR recognition andsignaling. This is achieved through the modulation of the orthosteric and allosteric binding sites of the adjacent protomer and of its G proteinactivation, its G protein selectivity, its signaling cascades with among others switching from G protein to ..-arrestin signaling and throughappearance of novel allosteric sites that may alter for instance G protein coupling and selectivity. GPCRs can also form complexes with ionchannelreceptors.The main focus in this mini hot topic issue is on the relevance of receptor complexes, such as A2A-D2 heteromers and NMDA-NTS1receptor interactions, for an improved understanding of the etiopathogenesis of Parkinson's disease, schizophrenia and cocaine addiction aswell as for the development of new pharmacological strategies. Furthermore, new hypothetical strategies for other pharmacologicalinterventions besides the classical approaches, are herein suggested.

Relevance of Dopamine D2/Neurotensin NTS1 and NMDA/Neurotensin NTS1 Receptor Interaction in Psychiatric and Neurodegenerative Disorders by S. Tanganelli, T. Antonelli, M.C. Tomasini, S. Beggiato, K. Fuxe, L. Ferraro (304-316).
The existence of functional NT/dopamine interactions in the central nervous system has been extensively documented. Amongothers, a possible molecular mechanism underlying the NT-induced modulation of dopamine release is a direct antagonistic NTS1/D2receptor interaction. More recently, neurochemical experiments also supported the existence of a possible interaction between NT and Nmethyl-d-aspartate (NMDA) receptors. In particular, it has been suggested that NT, by amplifying NMDA receptor signaling, could beinvolved in neurodegeneration.The present article attempts to provide a summary of current knowledge, mainly emerging from our studies, on the existence of receptorreceptorinteractions between NT receptor subtype 1 (NTS1) and dopamine D2 or NMDA receptors in the brain. Special emphasis isplaced on the pre and post-synaptic neurochemical mechanisms possibly underlying the involvement of these interactions in thephysiopathology of schizophrenia and acute neurodegenerative disorders.

The Importance of the Adenosine A2A Receptor-Dopamine D2 Receptor Interaction in Drug Addiction by M. Filip, M. Zaniewska, M. Frankowska, K. Wydra, K. Fuxe (317-355).
Drug addiction is a serious brain disorder with somatic, psychological, psychiatric, socio-economic and legal implications inthe developed world. Illegal (e.g., psychostimulants, opioids, cannabinoids) and legal (alcohol, nicotine) drugs of abuse create a complexbehavioral pattern composed of drug intake, withdrawal, seeking and relapse. One of the hallmarks of drugs that are abused by humans isthat they have different mechanisms of action to increase dopamine (DA) neurotransmission within the mesolimbic circuitry of the brainand indirectly activate DA receptors. Among the DA receptors, D2 receptors are linked to drug abuse and addiction because their functionhas been proven to be correlated with drug reinforcement and relapses. The recognition that D2 receptors exist not only as homomers butalso can form heteromers, such as with the adenosine (A)2A receptor, that are pharmacologically and functionally distinct from theirconstituent receptors, has significantly expanded the range of potential drug targets and provided new avenues for drug design in thesearch for novel drug addiction therapies. The aim of this review is to bring current focus on A2A receptors, their physiology andpharmacology in the central nervous system, and to discuss the therapeutic relevance of these receptors to drug addiction. We concentrateon the contribution of A2A receptors to the effects of different classes of drugs of abuse examined in preclinical behavioral experimentscarried out with pharmacological and genetic tools. The consequences of chronic drug treatment on A2A receptor-assigned functions inpreclinical studies are also presented. Finally, the neurochemical mechanism of the interaction between A2A receptors and drugs of abusein the context of the heteromeric A2A-D2 receptor complex is discussed. Taken together, a significant amount of experimental analysesprovide evidence that targeting A2A receptors may offer innovative translational strategies for combating drug addiction.

GPCR Heteromers and their Allosteric Receptor-Receptor Interactions by K. Fuxe, D.O. Borroto-Escuela, D. Marcellino, W. Romero-Fernandez, M. Frankowska, D. Guidolin, M. Filip, L. Ferraro, A.S. Woods, A. Tarakanov, F. Ciruela, L.F. Agnati, S. Tanganelli (356-363).
The concept of intramembrane receptor-receptor interactions and evidence for their existences were introduced in thebeginning of the 1980’s, suggesting the existence of receptor heterodimerization. The discovery of GPCR heteromers and the receptormosaic (higher order oligomers, more than two) has been related to the parallel development and application of a variety of resonanceenergy transfer techniques such as bioluminescence (BRET), fluorescence (FRET) and sequential energy transfer (SRET). The assemblyof interacting GPCRs, heterodimers and receptor mosaic leads to changes in the agonist recognition, signaling, and trafficking ofparticipating receptors via allosteric mechanisms, sometimes involving the appearance of cooperativity. The receptor interface in theGPCR heteromers is beginning to be characterized and the key role of electrostatic epitope-epitope interactions for the formation of thereceptor heteromers will be discussed. Furthermore, a "guide-and-clasp" manner of receptor-receptor interactions has been proposedwhere the "adhesive guides" may be the triplet homologies. These interactions probably represent a general molecular mechanism forreceptor-receptor interactions. It is proposed that changes in GPCR function (moonlighting) may develop through the intracellular loopsand C-terminii of the GPCR heteromers as a result of dynamic allosteric interactions between different types of G proteins and otherreceptor interacting proteins in these domains of the receptors. The evidence for the existence of receptor heteromers opens up a newfield for a better understanding of neurophysiology and neuropathology. Furthermore, novel therapeutic approaches could be possiblebased on the use of heteromers as targets for drug development based on their unique pharmacology.

DNA Interstrand Cross-Linking Agents and their Chemotherapeutic Potential by L. Brulikova, J. Hlavac, P. Hradil (364-385).
DNA interstrand cross-linking (ICL) agents are an important group of cytotoxic drugs with the capability of binding covalentlybetween two strands of DNA, thereby preventing vital processes such as replication or transcription in dividing cells. In anticancertherapy however, their potential is limited due to the resistance by various mechanisms. In order to develop highly effective antitumordrugs it is necessary to study both effective ICL formations and their subsequent repair mechanisms. This review presents an overview ofdevelopment over the past decade and the use of both well-known and new DNA interstrand cross-linking agents. Their potential inapplications especially as anticancer chemotherapeutics in the framework of current knowledge of repair mechanisms and developmentof combined chemotherapy is discussed.

Nitric Oxide: State of the Art in Drug Design by R.A.M. Serafim, M.C. Primi, G.H.G. Trossini, E.I. Ferreira (386-405).
Since the great discovery of Furchgott, Ignarro and Murad in the late 90´s, nitric oxide (NO) is considered one of the mostversatile endogenous molecules, which is involved in important signaling biochemistry pathways of the human body. Thus, it is directlyrelated to pathological processes and its over- or low-production is able to cause damage in systems that are involved. By using certainfunctional groups present in molecules that already have potential therapeutic value, hybrid compounds, by means of inclusion of NOdonors(e.g., ester nitrates, furoxans, benzofuroxans, NONOates, S-nitrosothiols, metal complexes), can be generated that have a NOrelease benefit along with maintaining the activity of the native drug. This approach has proved to be useful in many spheres ofMedicinal Chemistry, such as cardiovascular, inflammatory, bacterial, fungal, viral, parasitic, ocular diseases and cancer. Potent andselective nitric oxide synthase inhibitors are being designed, mainly through enzyme structure based process, however, due to highhomology between the isoforms, these studies have proved to be very difficult. The objective of the research is to achieve a balancebetween the release of therapeutic amounts of NO, especially in specific site of action, and maintaining the native drug activity. Thesearch for new and effective NO-donor hybrid drugs, as well as selective nitric oxide synthase inhibitors, is an important focus in moderndrug design in order to manipulate biochemical pathways involving NO that influence many dysfunctions of the human organism.

New Perspectives in Antiplatelet Therapy by A. Tello-Montoliu, E. Jover, J. Rivera, M. Valdes, D.J. Angiolillo, F. Marin (406-427).
Platelet activation is a complex mechanism of response to vascular injury and atherothrombotic disease, leading to thrombusformation. A wide variety of surface receptors -integrins, leucine-rich family receptors, G protein coupled receptors, tyrosine kinasereceptors- and intraplatelet molecules support and regulate platelet activation. They are potential targets of antiplatelet therapy for theprevention and treatment of arterial thrombosis. Despite the overall clinical benefit of established antiplatelet drugs targetingcyclooxigenase-1 (COX-1), glycoprotein integrin ..IIb..3, and the purinergic P2Y12 receptor of adenosine diphosphate, a significantproportion of treated patients continue to experience recurrent ischaemic events. This may be in partly attributed to insufficient inhibitionof platelet activation. In addition, it should not be underestimated that these drugs are not immune from bleeding complications.The substantial progress in understating the regulation of platelet activation has played a key role in the development of novel antiplateletagents. Current examples of drug under development and evaluation include: novel P2Y12 receptor inhibitors (prasugrel, ticagrelor,cangrelor, and elinogrel), thrombin receptor PAR-1 antagonists (vorapaxar, atopaxar), new integrin glycoprotein IIb/IIIa inhibitors, andinhibitors targeting the thromboxane receptor (TP), phosphodiesterases, the collagen receptor glycoprotein VI, and intraplatelet signallingmolecules. This review summarizes the mechanisms of action and current clinical evaluation of these novel antiplatelet agents.

Emerging Targets for the Pharmacological Treatment of Depression: Focus on Melatonergic System by Mario Catena-Dell’Osso, Donatella Marazziti, Francesco Rotella, Cesario Bellantuono (428-437).
Depression is a disabling condition which adversely affects a person’s family, social and work life, and that is associated witha heavy burden to society. Although the available antidepressants have shown their effectiveness and have greatly improved theprognosis of the disorder, the current management of depression is far from being satisfactory. In the last years, besides the classicalresearch involving serotonin, norepineprine and dopamine, non-monoaminergic mechanisms have been explored in the attempt todiscover new antidepressants. One such innovative approach focused on melatonergic system, as melatonin is involved in synchronizingcircadian rhythms, which are known to be altered in depression. This narrative review aims to provide a comprehensive overview ofdifferent aspects of the melatonergic system, including biochemical and anatomical characteristics, impact on the sleep/wake system, andimplications for the treatment of depression. In particular, the observation that melatonin may promote sleep and synchronize the internalclock led to development of high-affinity agonists for melatonin receptors (MT). Agomelatine, a naphthalene bioisostere of melatonin,which combines a potent MT1 and MT2 agonism with 5-HT2C receptor antagonism, has been found to be effective in the treatment ofdepressive and anxiety symptoms associated with major depression, with rapid and beneficial effects on the regulation of sleep continuityand quality. If substantiated by further evidence, the observation that melatonergic system dysfunctions contribute to the development ofdepression, as well as that the antidepressant action of agomelatine is linked to its binding properties to MT1/MT2 receptors, might opennew avenues for the discovery of antidepressive agents.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell hyperactivity and defective T-cellfunction, and several cytokine aberrations, with high titer production of autoantibodies and clinical involvement in multiple organsystems. It can present with a wide variety of symptoms, most commonly involving the skin, joints, kidneys, and blood vessels. Patientswith mild SLE can be treated with non-steroidal antiinflammatory drugs and antimalarials. Corticosteroids, azathioprine andcyclophosphamide, remain important for long term management of most patients with active disease. In recent years, significant progressin molecular and cellular biology of SLE has resulted in a better characterization and understanding of the biology and prognosis of thisdisease. These achievements have provided new opportunities for the development of innovative, more effective, therapies. Novel agentspotentially useful in the treatment of patients with SLE include tolerogens, monoclonal antibodies and other agents. Tolerogens aresynthetic molecules that can bind and cross-link autoantibodies on reactive B-cell surface, promoting B-cell depletion or inactivity. Ananti-DNA antibody based peptide, pCons, might have also therapeutic efficacy in SLE patients who are positive for anti-DNA antibodies.In addition, prasterone, a proprietary synthetic dehydroepiandrosterone product is under investigation for the treatment of SLE. Blockadeof TLR9 with specific G-rich DNAoligonucleotids also suppresses lupus activity. Several newer mAbs have been developed and arebeing evaluated in phase I/II clinical trials. These include newer anti-CD20 mAbs, anti-cytokine therapies, anti-BLys mAbs and anti-C5mAbs. Most of the new agents which could be potentially useful in the treatment of patients with SLE need further laboratoryinvestigations and clinical trials. In this review, promising new agents, potentially useful in SLE, are presented.

Transforming Growth Factor β Signaling Perturbation in the Loeys-Dietz Syndrome by A. Pezzini, E. Del Zotto, A. Giossi, I. Volonghi, P. Costa, A. Padovani (454-460).
The transforming growth factor β (TGFβ) superfamily consists of multipotential secreting cytokines that mediate many keyevents in normal cellular growth and development, including differentiation, proliferation, motility, organization and death. TGFβs act asligand for 3 classes of cell surface receptors, the transmembrane serine-threonine kinase receptors, TGFβ receptor type I (TGFβRI) andtype 2 (TGFβRII), and TGFαRIII receptors which include an ubiquitous extracellular β-glycan and the membrane glycoprotein endoglin(CD105). Binding of TGFαs to their receptors initiates diverse cellular responses resulting in the phosphorilation of Smad proteins, whichthen translocate to the nucleus and regulate the transcription of target genes. Perturbation of TGFα signaling has been implicated invarious human disorders including cancer, fibrosis and auto-immune diseases. Recently, mutations in TGFβR1 and TGFβR2 genes havebeen found in association with a continuum of clinical features with widespread vascular involvement. The extreme of clinical severity isrepresented by the Loeys-Dietz syndrome (LDS), an autosomal dominant disorder characterized by hypertelorism, bifid uvula, and/orcleft palate, and aggressive arteriopathy causing arterial tortuosity as well as life-threatening complications such as vascular aneurysmsand dissections. Elastin disarray, loss of elastic fibre architecture and increased collagen expression in the arterial wall are the pathologichallmark of LDS. In the present review article we will provide details on the activation of TGFβ cascade, on the clinical features of LDS,as well as on the mechanisms of TGFβ signaling perturbation leading to this condition and the potential role of the antagonism of TGFβactivity in disease management.