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Tesi etd-02232009-124745


Thesis type
Tesi di dottorato di ricerca
Author
VANNI, MICHAEL
email address
michael.vanni@alice.it
URN
etd-02232009-124745
Title
New P-glycoprotein inhibitors: potential tools to reduce Multidrug Resistance
Settore scientifico disciplinare
CHIM/08
Corso di studi
SCIENZA DEL FARMACO E DELLE SOSTANZE BIOATTIVE
Commissione
Relatore Prof. Balsamo, Aldo
Parole chiave
  • P-glycoprotein inhibitors
  • Multidrug Resistance
Data inizio appello
11/03/2009;
Consultabilità
completa
Riassunto analitico
One of the classical protection mechanism of cancer cells involves an increased expression of drug efflux transport proteins like P-glycoprotein (P-gP). P-gP is an ABC drug efflux transporter which is fisiologically express in many tissues such as the blood-brain-barrier (BBB) where it is involved in the protection of the CNS from potentially toxic agents.<br>This protein is able to transport a wild structural different substrates, including many drugs used for a wild range of therapeutic applications. Therefore, the research of safe and effective P-gP inhibitors endowed of high selectivity and potency represent a great challenge in medicinal chemistry. In particular, the possibility to have selective molecules able to inhibit this protein could be useful to modulate the pharmacological behaviour of drugs including those used for chemo-therapy-resistant tumors.<br>Up to now many agents modulating P-gP have been characterized including channel blockers, calmodulin antagonists, immunosuppressant and protein kinase inhibitors but all these compounds produced disappointing results in vivo because the use of high dose resulting in unacceptable toxicity. Some new drugs such as biricodar, tariquidar and elacridar have satisfactory inhibitory effects on P-gP. This latter displayed a high potency for P-gP transporter but it also inhibited breast cancer resistance protein (BCPR).<br>On the basis of computational studies which suggested a general pharmacophore of a substrate/inhibitor of P-gP transporter, in which both a planar aromatic domain and a presence of a basic nitrogen atom within an extended side chain are described, we designed and synthesised new compounds. <br>These molecules possessed a benzylethereal side chain substituted by aliphatic spacer of 2, 3, or 4 methylenes linked to an arylpiperazine nucleus. All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br>All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. All the synthesized compounds have been tested in vitro to evaluated the inhibitor activity on Caco2 cells in which P-gP is overexpressed and the best results have been obtained for compounds having a four methylene chain. Unfortunatelly, as expected, all arylpiperazine classes displayed hight serotoninergic 5-HT1A and dopaminergic D2 receptor affinities.<br>In order to improve P-gP affinity and eliminate serotoninergic and dopaminergic activities some structural manipulations on these derivatives have been carried out such as the substitution of the aryl and arylpiperazine moieties with a methylic and tetrahydroisoquinoline nucleuses respectively. <br>Besides new ligand series arylmethyloxyphenyl1,2,3 were prepared by removing the alkylpiperazinic ring and linking arylmethyl groups directly to the phenoxyalkyl nucleous. Moreover the replacemant of the oxygen atom with a nitrogen one led to arylmethylaminophenyl2 derivatives more potent than the oxygen-analogues, which behaved as elacridar but displayed a more simple structure.<br>However, in N-methylpiperazine series the spacer length poorly influenced the P-gP inhibitory activity.<br>On other hand, analogously to the arylpiperazine-derivatives, also within the tetrahydroisoquinoline-derivatives, the spacer elongation improved P-gP inhibitory activity.<br>Since the limit of P-gP inhibitors such as elacridar is the poor selectivity toward other ABC transporters, in particular the BCRP pump, all the active compounds were tested for their ability to inhibit [3H]-mitoxantrone, a specific BCRP substrate. The results showed that only arylmethylaminephenyl derivatives displayed a good BCRP inhibition activity.<br>These results led us to consider the 2-[(3-methoxyphenylethyl)phenoxy]- fragment, present in the more selective P-gP inhibitors, the pivotal molecular basis to design novel P-gP inhibitors. <br><br><br><br>
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