Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and interaction and restricted, repetitive patterns of behavior, ...interests, and activities. Various factors are involved in the etiopathogenesis of ASD, including genetic factors, environmental toxins and stressors, impaired immune responses, mitochondrial dysfunction, and neuroinflammation. The heterogeneity in the phenotype among ASD patients and the complex etiology of the condition have long impeded the advancement of the development of pharmacological therapies. In the recent years, the integration of findings from mouse models to human genetics resulted in considerable progress toward the understanding of ASD pathophysiology. Currently, strategies to treat core symptoms of ASD are directed to correct synaptic dysfunctions, abnormalities in central oxytocin, vasopressin, and serotonin neurotransmission, and neuroinflammation. Here, we present a survey of the studies that have suggested molecular targets for drug development for ASD and the state-of-the-art of medicinal chemistry efforts in related areas.
The serotonin receptor subtype 5 HT(1A) was one of the first serotonin receptor subtypes pharmacologically characterized. Over the last twenty years the 5 HT(1A) receptor has been the object of ...intense research efforts as witnessed by the 5 HT(1A) acting drugs marketed as anxiolytics. In recent years, several new chemical entities targeting the 5 HT(1A) receptor (alone or in combination with other molecular targets) have been proposed for novel therapeutic indications (neuroprotection, cognitive impairment, Parkinson Disease and related disorders, pain treatment). The present review will focus on those 5 HT(1A) receptor agents that entered preclinical trials starting from 2000.
With the aim of contributing to the development of novel antitumor agents, high-affinity σ2 receptor agonists were developed, with ...6,7-dimethoxy-2-4-1-(4-fluorophenyl)-1H-indol-3-ylbutyl-1,2,3,4-tetrahydroisoquinoline (15) and 9-4-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)butyl-9H-carbazole (25) showing exceptional selectivity for the σ2 subtype. Most of the compounds displayed notable antiproliferative activity in human MCF7 breast adenocarcinoma cells, with similar activity in the corresponding doxorubicin-resistant MCF7adr cell line. Surprisingly, a few compounds, including 25, displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug-resistant tumors. All of the compounds showed interaction with P-glycoprotein (P-gp), and 15 and 25, with the greatest activity, were able to revert P-gp-mediated resistance and reestablish the antitumor effect of doxorubicin in MCF7adr cells. We therefore identified a series of σ2 receptor agonists endowed with intriguing antitumor properties; these compounds deserve further investigation for the development of alternate strategies against multidrug- resistant cancers.
We have determined the pharmacological profile of the new serotonin 5-HT
7
receptor agonist
N
-(4-cyanophenylmethyl)-4-(2-diphenyl)-1-piperazinehexanamide (LP-211). Radioligand binding assays were ...performed on a panel of 5-HT receptor subtypes. The compound was also evaluated
in vivo
by examining its effect on body temperature regulation in mice lacking the 5-HT
7
receptor (5-HT
7
−/−
) and their 5-HT
7
+/+
sibling controls. Disposition studies were performed in mice of both genotypes. It was found that LP-211 was brain penetrant and underwent metabolic degradation to 1-(2-diphenyl)piperazine (RA-7).
In vitro
binding assays revealed that RA-7 possessed higher 5-HT
7
receptor affinity than LP-211 and a better selectivity profile over a panel of 5-HT receptor subtypes.
In vivo
it was demonstrated that LP-211, and to a lesser degree RA-7, induced hypothermia in 5-HT
7
+/+
but not in 5-HT
7
−/−
mice. Our results suggest that LP-211 can be used as a 5-HT
7
receptor agonist
in vivo
.
In recent years, several PET tracers for monitoring the activity and expression of P-gp at the BBB have been tested. P-gp substrates such as (11)Cverapamil and (11)Cloperamide can be employed to ...visualize P-gp activity, but they display a moderate baseline uptake in the brain and formation of radiolabeled metabolites which hamper the interpretation of PET data. P-gp inhibitors such as (11)Celacridar, (11)Claniquidar and (11)Ctariquidar have been tested to investigate P-gp expression and the results need further investigation. Recently, we developed MC18, MC266 and MC80, that have been characterized as an inhibitor, substrate and inducer of P-gp both by in vitro assays and in the everted gut sac method. These compounds have been radiolabelled with (11)C and been evaluated in vivo. In the present review, we compare the outcome of biological in vitro assays and the corresponding in vivo PET data for the P-gp inhibitors (11)CMC18 and (11)Celacridar, the P-gp substrates (11)CMC266 and (11)Cverapamil, the P-gp inducer (11)CMC80 and the P-gp modulator cyclosporin A. Since a satisfactory overlap was found comparing in vivo results and the corresponding in vitro findings, the proposed biological in vitro assays could be predictive for the in vivo PET data of novel radiotracers. PET tracers could be employed for various purposes: radiolabeled P-gp inhibitors to monitor decreased expression of P-gp at the BBB in neurodegenerative disorders such as Alzheimer's and Parkinson's disease; and radiolabeled P-gp substrates with a high baseline uptake to monitor increased expression of P-gp in epileptic foci.
P-glycoprotein is an ATP-binding cassette transporter involved in drug absorption, distribution and excretion. It pumps a wide range of xenobiotic compounds out of the cells and plays a crucial role ...in Multi Drug Resistance. Moreover, recent studies have demonstrated that changes in P-gp function and/or expression at the blood brain barrier are implicated in the pathogenesis of neurological disorders such as therapy-refractory epilepsy, Alzheimer's and Parkinson's disease. In the last decades the studies have been addressed to the discovery of potent P-gp inhibitors able to revert pharmacoresistance and to the development of PET tracers to detect P-gp activity and expression for an early diagnosis and therapy monitoring of neurodegenerative disease. However, clinical trials have reported only limited success in reversing MDR and radiolabeled ligands were not actually useful to study differences of transporter function in different brain regions due to their low brain uptake. The difficulties into the discovery of new ligands is due to the use of different experimental assays, to the fact that P-gp is highly flexible protein with different binging sites and available crystallographic structures for the protein have inadequate resolution. To overcome these limitations research groups prefer computational approaches such as homology models in their structure-based design or ligand-based methodologies. A recent approach aimed to identify ligands which can interrupt ATP-binding and hydrolysis by P-gp, by interacting at the NBDs of the protein. In this review results from radiolabeled, substrates and inhibitors, for monitoring the activity and expression of P-gp, respectively, are presented.
A series of furoxan derivatives were studied for their ability to interact with P-gp and MRP1 transporters in MDCK cells overexpressing these proteins. 3-Phenylsulfonyl substituted furoxans emerged ...as the most interesting compounds. All of them were capable of inhibiting P-gp, and a few also were capable of inhibiting MRP1. Substituents at the 4-position of 3-phenylsulfonylfuroxan scaffold were able to modulate the selectivity and the intensity of inhibition. In some cases, they reverted MRP1 inhibitor activity, namely, they were capable of potentiating MRP1 dependent efflux. When compounds 16 and 17 were coadministered with doxorubicin, they restored a high degree of the activity of the antibiotic. Preliminary immunoblotting studies carried out on these two compounds indicate that they are capable of nitrating P-gp, which in this form is likely unable to efflux the antibiotic.
ABC pumps and their role in active drug transport Colabufo, Nicola A; Berardi, Francesco; Contino, Marialessandra ...
Current topics in medicinal chemistry,
02/2009, Letnik:
9, Številka:
2
Journal Article
Recenzirano
Pharmacokinetic limitations affect drug bioavailability determining the loss or the reduction of the pharmacological effects. The Gastro Intestinal tract (GI) and the Blood Brain Barrier (BBB) are ...the most important restrictive and selective physiological lines of defense of the organism. Although several parameters such as LogP, LogD and K(a) have been extensively employed for determining drug bioavailability, the active transports, present in these biological barriers, play an important role for dosing and limiting cell drugs concentration. In particular, ATP Binding Cassette (ABC) transporters are involved in the active transport both in GI and BBB. Their strategic activity and biochemical and pharmacological role are herein treated.
σ Ligands have recently been shown to have cytotoxic activity, to induce ceramide-dependent/caspase-independent apoptosis,
and to down-regulate P-glycoprotein (P-gp) mRNA levels in some mouse and ...human models. In this study, we verified whether
a mixed σ 2 agonist/σ 1 antagonist, PB28, was able to have antitumor activity and to enhance anthracycline efficacy in two human breast cancer cell
lines, MCF7 and MCF7 ADR, both characterized by significant σ 2 receptor expression, by high and low σ 1 receptor expression, and low and high P-gp expression, respectively. In both cell lines, PB28 showed high σ 2 receptor affinity and low σ 1 receptor affinity; furthermore, it inhibited cell growth with a clear effect at 48 hours (IC 50 in nanomolar range), a consistent time exposure-independent increase of G 0 -G 1 -phase fraction (of ∼20% of both cell lines) and caspase-independent apoptosis (15% increased after 1-day drug exposure).
PB28 also reduced P-gp expression in a concentration- and time-dependent manner (∼60% in MCF7 and 90% in MCF7 ADR). We showed
also a strong synergism between PB28 and doxorubicin by adopting either simultaneous or sequential schedules of the two drugs.
We suggest that this synergism could depend on PB28-induced increase of intracellular accumulation of doxorubicin (∼50% in
MCF7 and 75% in MCF7 ADR by flow cytometry analysis). In conclusion, we suggest that the σ 2 agonist PB28 could be an interesting antitumor agent either in monotherapy or in combination with conventional drugs. Mol
Cancer Ther 2006;5(7):1807–16
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