1,721,183 research outputs found
Peptide derivatives as agonists or antagonists of formylpeptide receptors: analysis of their effects on neutrophils
No full textThe effects of peptide derivatives as agonists or antagonists of formylpeptide receptors are described, taking into account the related cellular responses by neutrophils. These effects are related to the structure of peptide derivatives, some of which are potent anti HIV-1 agents. Finally, formylpeptide receptor models are depicted
Adenosine A1 receptor: Analysis of the potential therapeutic effects obtained by its activation in the central nervous system
No full textAdenosine modulates several physiological functions in the CNS and in peripheral tissues via membrane receptors which have been classified into four adenosine subtypes. A(1) activation produces neuronal depression: this inhibition allows A(1) agonists to produce ischemic tolerance and protection in neuronal tissue. In order to selectively reproduce these effects, several A(1) selective ligands have been synthesised and evaluated to understand how they interact with the adenosine A(1) receptor. The investigation methods include SAR studies using native and chemically modified A(1) receptors, molecular cloning of native and mutant adenosine A(1) receptors, molecular modeling and thermodynamic analysis of drug-receptor interaction. Despite the great quantity of information available on the adenosine A(1) receptor, no A(1) agonist has so far entered in clinical use against brain diseases in view of the side effects; moreover selective A(1) agonists appear to be poorly adsorbed into the brain and can be quickly degraded in vivo or in the whole blood. In an attempt to overcome these problems studies have been undertaken dealing with the use of partial agonists to inhibit side-effects and the employment of prodrugs to increase stability and diffusion through lipid barriers of A(1) ligands. Other attempts involve either the use of A(1) receptor enhancers as modulators able to locally enhance the action of endogenously produced adenosine, or the encapsulation of A(1)agonists in drug delivery systems targeted to the brain. In this review, these approaches will be described together with the effects of adenosine A(1) receptor ligands and their binding mechanisms on the central nervous system
Prodrugs, micro- and nano-particulate systems: are they suitable tools for drug targeting into the central nervous system?
No full textHydrophilic drugs, or neuroactive agents characterized by high molecular weight, do not have
the physico-chemical properties required for passive diffusion across the blood brain barrier (BBB).
The prodrug approach by lipidization of hydrophilic drugs can allow to sensibly increase their
permeability across BBB but, unfortunately, this phenomenon is often not associated to an effective
entry into the brain of the lipidized drugs.
Carrier mediated transporters (CMT), able to transfer essential nutrients and hormones from
the bloodstream to the central nervous system (CNS), can be employed for the brain targeting of
appropriated designed prodrugs. This approach consists on the chemical modification of a drug into a
“pseudonutrient” or, differently, on drug conjugation to essential nutrients transported by CMT
systems. In particular, prodrugs able to act as substrates of neutral amino acids (LAT1), glucose
(GLUT1) or vitamin C (SVCT2) transporters appear promising for the uptake of neuroactive drugs in
the brain from the bloodstream.
On the other hand, it has been understood that active efflux transporters (AET) can have a
very important role in extruding from the brain not only prodrugs obtained by lipidization processes,
but also lipophilic drugs. AET expression maintains in general the homeostasis in healthy tissues and
in the blood–brain barrier it often prevents drugs from reaching the brain. Inhibition of AETs could
therefore be a valuable solution for the brain targeting of neuroactive drugs, but nonselective longterm
AET blocking can be harmful toward healthy tissues and, in particular, the brain itself. As a
consequence, only the circumvention of efflux pumps appears to be a valuable strategy for targeting
neuroactive drugs in the CNS.
The knowledge of the molecular aspects that regulate the activity of the CMT and AET
systems for the transport of their substrates, appear of great importance in order to evaluate the
molecular keys for the design of prodrugs efficacious in the brain targeting. These studies can be
performed in vitro, by employing monocellular layers able to selectively express on their membranes
CMT or AET systems. The design of new prodrugs able to elude the efflux pumps can offer therefore
new opportunities for brain targeting.
Polymeric nanoparticles with appropriate surface properties can target the CNS, allowing the
encapsulated drugs to exert their therapeutic effects against brain diseases. Each single nanoparticle
can incorporate the neuroactive drugs and the targeting agents able to promote their BBB permeation
via receptor mediated transport (RMT) systems. It is also known that poly(butyl cyanoacrylate)
(PBCA) or poly(lactic-co-glycolic acid) (PLGA) nanoparticles coated with certain surfactants, such
as polysorbate 80 (Tween 80) or poloxamer 188 (Pluronic F68), are able to induce the brain targeting
of their loaded neuroactive drugs.
Polymeric microparticles can be employed as promising formulations for nasal administrations
that allow their incapsulated drugs to target the CNS by eluding the BBB. In this case, the polymer
itself that constitutes the particles can have properties able to enhance the drug permeation across the
olfactory mucosa.
A new promising strategy for brain targeting of neuroactive drugs is represented by the
encapsulation in nano- or micro-particulate systems of prodrugs able to elude the efflux pumps
(AET), thus increasing the concentration of neuroactive agents in the CNS after non-invasive
administration of the particles. As an example, zidovudine (AZT) is an antiviral drug employed
against HIV, but unable to reach the brain being substrate of AET systems. HIV is instead able to
easily invade the CNS that becomes a sanctuary of the virus from which the periphery can be
continuously re-infected. The conjugation of AZT with a bile acid (ursodeoxycholic acid, UDCA),
allows to obtain a prodrug (UDCA-AZT) able to elude the AET systems expressed by BBB. Solid
lipid microparticles loaded with UDCA-AZT constitute a nasal formulation able to induce the uptake
of the prodrug in the cerebro spinal fluid (CSF). Upon uptake, the prodrug appears able to prolong its
permanence in the CSF, in accordance with its ability to elude the AET systems
Dopamine-Responsive Isoforms of Adenylyl Cyclase as Coincidence Detectors in Development and Function of Dopaminergic Neurons
No full textAccumulating evidence on molecular mechanisms leading to the differentiation of neurons with retained dopaminergic fate and function suggests the induction of such differentiation as a potential form of treatment of many neurodegenerative disorders, such as Parkinson's disease (PD) and schizophrenia. Signals conveyed by the effector enzyme adenylyl cyclase (AC) appear to be important for survival or mature functioning of neurons. Indeed, although drugs interfering with this pathway have been traditionally considered to target membrane receptors coupled to G-proteins, the ACs can be thought as new interesting “druggable” target, being known to work as signaling catalysts. We discuss herein the advance of isoform-selective stimulator and/or inhibitor compounds for AC that could lead to cell-specific pharmacotherapeutics for treating dopamine (DA)-mediated disorders, including neuropsychiatric, neurodegenerative and neuroapoptotic diseases. In this context, the calcium- and DA-sensitive isoforms of AC are considered as potential key cues for dopaminergic neuronal patterning and maintenance. In particular, cell lines differentiating dopaminergic properties and expressing selective DA- and calcium-sensitive isoforms of AC are taken into account for new therapeutic and experimental tools in inducing regenerative processes or to evaluate how cAMP signals discriminate among sympatho-adrenal heterogenic lineages of neurons
De novo analysis of receptor binding affinity data of xanthine adenosine receptor antagonist
No full textThe receptor binding affinity data to adenosine A1 and A2 receptors of a wide series of xanthine derivatives have been analyzed by means of the Free-Wilson model. The analysis of the individual group contribution shows, for both A1 and A2 receptors, the primary importance of the presence of bulky substituents at position 8 for an optimum receptor binding. Moreover, considering the different a(ij) contributions of bulky substituents at position 8 for affinity to A1 with respect to A2 receptors, this position appears to be the most important for the synthesis of highly A1 selective xanthine derivatives. Moreover the analysis of group contributions for other substitution positions of the xanthine moiety allows to state that suitable substitutions at positions 3 and 7 could confer some degree of A2 selectivity
Adenylyl cyclases as innovative therapeutic goals.
No full textPharmacological modulation of intracellular cyclic AMP (cAMP) signalling could provide new therapeutic and experimental tools. Although drugs interfering with this pathway have traditionally targeted membrane receptors, the effector enzyme adenylyl cyclase (AC), which functions as a signalling catalyst, also presents an interesting target. Thus, development of isoform
selective stimulator and/or inhibitor compounds for AC could lead to organ-specific pharmacotherapeutics for treating heart failure, cancer, and neurodegenerative diseases. In this review, the potential of AC as the object of drug therapy is discussed
Retinal pigment epithelial cells as a therapeutic tool and target against retinopathies
No full textRetinal pigment epithelium (RPE) is a cell monolayer essential for photoreceptor function and forming the blood–retinal barrier. RPE and retinal neurons share the same origin and a polarized cytoarchitecture. Several factors determine the phagocytosis and permeability of RPE, influencing photoreceptor renewal and drug delivery, efficacy and toxicity. Adult human RPE expresses neuronal markers in vitro, indicating a potential transdifferentiation. Degeneration of the RPE leads to death of photoreceptors and retinal neurons, resulting in the vision loss of retinopathy. Here, we suggest tools for cell engineering to discover new ways for activating the endogenous regeneration of barrier functions and/or of the retinal precursors in RPE cells
CPA-loaded polymeric nanoparticles prepared via a non-aqueous nanoprecipitation method
No full textPurpose: A novel non-aqueous nanoprecipitation method was used to achieve the encapsulation of a small weight hydrophilic drug (N6-cyclopentyladenosine, CPA) in PLA or PLGA nanoparticles. The drug release properties and the size characteristics of nanoparticles were investigated.
Methods: Nanoparticles were prepared by a nanoprecipitation method using an organic solvent in the presence of Tween 80. The obtained nanoparticles were purified by ultrafiltration, suspended in water by sonication and freeze-dried. The release studies were performed in water and drug stability was evaluated in physiologic fluids.
Results: The freeze-dryed nanoparticles re-dispersed by sonication produced a monodispersed colloidal system. The drug loading capability obtained by this technique appeared considerably higher than that found by the conventional encapsulation methods. Using either PLA or PLGA polymer, a biphasic drug release profile was observed. The extent of the first burst release was dependent on the initial amount of drug in the preparation. The second release phase was slow and characterized by a probable diffusion mechanism. The rate of the second drug release phase can be accelerated or retarded by the presence of a filler (such as lauric acid) or a pore former agent (such as Tween 20), respectively.
Conclusions: The novel method used allows an efficient drug loading to be obtained along with a prolonged drug release, despite the small size of the nanoparticles and the hydrophilic nature of the drug. The most interesting feature of this novel method is not only the possibility to produce high loaded nanoparticles but also modulate their drug release rate
Can pharmaceutical co-crystals provide an opportunity to modify the biological properties of drugs?
No full textPoorly soluble and/or permeable molecules jeopardize the discovery and development of innovative medicines. Pharmaceutical co-crystals, formed by an active pharmaceutical substance (API) and a co-crystal former, can show enhanced dissolution and permeation values compared with those of the parent crystalline pure phases. It is currently assumed that co-crystallization with pharmaceutical excipients does not affect the pharmacological activity of an API or, indeed, might even improve physical properties such as solubility and permeability. However, as we highlight here, the biological behavior of co-crystals can differ drastically with respect to that of their parent physical mixtures
Odorants could elicit repair processes in melanized neuronal and skin cells
No full textThe expression of ectopic olfactory receptors (ORs) in melanized cells, such as the human brain nigrostriatal dopaminergic neurons and skin melanocytes, is here pointed out. ORs are recognized to regulate skin melanogenesis, whereas OR expression in the dopaminergic neurons, characterized by accumulation of pigment neuromelanin, is downregulated in Parkinson's disease. Furthermore, the correlation between the pigmentation process and the dopamine pathway through α-synuclein expression is also highlighted. Purposely, these ORs are suggested as therapeutic target for neurodegenerative diseases related to the pigmentation disorders. Based on this evidence, a possible way of turning odorants into drugs, acting on three specific olfactory receptors, OR51E2, OR2AT4 and VN1R1, is thus introduced. Various odorous molecules are shown to interact with these ORs and their therapeutic potential against melanogenic and neurodegenerative dysfunctions, including melanoma and Parkinson's disease, is suggested. Finally, a direct functional link between olfactory and endocrine systems in human brain through VN1R1 is proposed, helping to counteract female susceptibility to Parkinson's disease in quiescent life
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