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The big data challenge: and how polypharmacology supports the translation from pre-clinical research into clinical use against neurodegenerative diseases and beyond
Get PDFMedicinal polypharmacology: a scientific glossary of terminology and concepts
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Medicinal polypharmacology: exploration and exploitation of the polypharmacolome in modern drug development
Get PDFAbstract At the core of complex and multifactorial human diseases, such as cancer, metabolic syndrome, or neurodegeneration, are multiple players that cross‐talk in robust biological networks which are intrinsically resilient to alterations. These multifactorial diseases are characterized by sophisticated feedback mechanisms which manifest cellular imbalance and resistance to drug therapy. By adhering to the specificity paradigm (“one target‐one drug concept”), research focused for many years on drugs with very narrow mechanisms of action. This narrow focus promoted therapy ineffectiveness and resistance. However, modern drug discovery has evolved over the last years, increasingly emphasizing integral strategies for the development of clinically effective drugs. These integral strategies include the controlled engagement of multiple targets to overcome therapy resistance. Apart from the additive or even synergistic effects in therapy, multitarget drugs harbor molecular‐structural attributes to explore orphan targets of which intrinsic substrates/physiological role(s) and/or modulators are unknown for future therapy purposes. We designated this multidisciplinary and translational research field between medicinal chemistry, chemical biology, and molecular pharmacology as ‘medicinal polypharmacology’. Medicinal polypharmacology emerged as alternative approach to common single‐targeted pharmacology stretching from basic drug and target identification processes to clinical evaluation of multitarget drugs, and the exploration and exploitation of the ‘polypharmacolome’ is at the forefront of modern drug development research.Deutsche Forschungsgemeinschaft https://doi.org/10.13039/50110000165
Transport of Small Aliphatic Amines by Polyspecific Solute Carriers: Deciphering Structure–Function Relationships
No full textTools and drugs for uracil nucleotide-activated P2Y receptors
Get PDFP2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14, which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y2 (UTP, also ATP and dinucleotides), P2Y4 (UTP), P2Y6 (UDP), and P2Y14 (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2Y2R agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2Y2R antagonist is AR-C118925 (10-01). For studies of the P2Y4R, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) is a selective antagonist. Several potent P2Y6R agonists have been developed including 5-methoxyuridine 5'-O-((Rp)α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2Y6R antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2Y14R agonist is available, while PPTN (10-14) represents a potent and selective P2Y14R antagonist. The radioligand [3H]UDP can be used to label P2Y14Rs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases
The necessity for polypharmacological research – an editorial on 'Network Polypharmacology of ATP-binding Cassette (ABC) and Solute Carrier (SLC) Transporters' [Editorial]
Get PDFStereoselectivity in the Membrane Transport of Phenylethylamine Derivatives by Human Monoamine Transporters and Organic Cation Transporters 1, 2, and 3
No full textStereoselectivity is well known and very pronounced in drug metabolism and receptor binding. However, much less is known about stereoselectivity in drug membrane transport. Here, we characterized the stereoselective cell uptake of chiral phenylethylamine derivatives by human monoamine transporters (NET, DAT, and SERT) and organic cation transporters (OCT1, OCT2, and OCT3). Stereoselectivity differed extensively between closely related transporters. High-affinity monoamine transporters (MATs) showed up to 2.4-fold stereoselective uptake of norepinephrine and epinephrine as well as of numerous analogs. While NET and DAT preferentially transported (S)-norepinephrine, SERT preferred the (R)-enantiomer. In contrast, NET and DAT showed higher transport for (R)-epinephrine and SERT for (S)-epinephrine. Generally, MAT stereoselectivity was lower than expected from their high affinity to several catecholamines and from the high stereoselectivity of some inhibitors used as antidepressants. Additionally, the OCTs differed strongly in their stereoselectivity. While OCT1 showed almost no stereoselective uptake, OCT2 was characterized by a roughly 2-fold preference for most (R)-enantiomers of the phenylethylamines. In contrast, OCT3 transported norphenylephrine and phenylephrine with 3.9-fold and 3.3-fold preference for their (R)-enantiomers, respectively, while the para-hydroxylated octopamine and synephrine showed no stereoselective OCT3 transport. Altogether, our data demonstrate that stereoselectivity is highly transporter-to-substrate specific and highly diverse even between homologous transporters.Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)research program of the University Medical Center, University of GöttingenOpen Access Publication Funds of the Göttingen Universit
Cellular uptake of psychostimulants: are high- and low-affinity organic cation transporters drug traffickers?
Get PDFPsychostimulants are used therapeutically and for illegal recreational purposes. Many of these are inhibitors of the presynaptic noradrenaline, dopamine, and serotonin transporters (NET, DAT, and SERT). According to their physicochemical properties, some might also be substrates of polyspecific organic cation transporters (OCTs) that mediate uptake in liver and kidneys for metabolism and excretion. OCT1 is genetically highly polymorphic, with strong effects on transporter activity and expression. To study potential interindividual differences in their pharmacokinetics, 18 psychostimulants and hallucinogens were assessed in vitro for transport by different OCTs as well as by the high-affinity monoamine transporters NET, DAT, and SERT. The hallucinogenic natural compound mescaline was found to be strongly transported by wild-type OCT1 with a K m of 24.3 µM and a v max of 642 pmol × mg protein−1 × min−1. Transport was modestly reduced in variants 2 and 7, more strongly reduced in 3 and 4, and lowest in 5 and 6, while 8 showed a moderately increased transport capacity. The other phenylethylamine derivatives methamphetamine, para-methoxymethamphetamine, (-)-ephedrine, and cathine ((+)-norpseudoephedrine), as well as dimethyltryptamine, were substrates of OCT2 with K m values in the range of 7.9–46.0 µM and v max values between 70.7 and 570 pmol × mg protein−1 × min−1. Affinities were similar or modestly reduced and the transport capacities were reduced down to half in the naturally occurring variant A270S. Cathine was found to be a substrate for NET and DAT, with the Km being 21-fold and the v max 10-fold higher for DAT but still significantly lower compared to OCT2. This study has shown that several psychostimulants and hallucinogens are substrates for OCTs. Given the extensive cellular uptake of mescaline by the genetically highly polymorphic OCT1, strong interindividual variation in the pharmacokinetics of mescaline might be possible, which could be a reason for highly variable adverse reactions. The involvement of the polymorphic OCT2 in the renal excretion of several psychostimulants could be one reason for individual differences in toxicity.Open-Access-Publikationsfonds 202
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