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Lacivita, E.a , Podlewska, S.b  c , Speranza, L.d , Niso, M.a , Satała, G.b , Perrone, R.a , Perrone-Capano, C.d  e , Bojarski, A.J.b , Leopoldo, M.a 
Structural modifications of the serotonin 5-HT7 receptor agonist N -(4-cyanophenylmethyl)-4-(2-biphenyl)-1-piperazinehexanamide (LP-211) to improve in vitro microsomal stability: A case study
(2016) European Journal of Medicinal Chemistry, 120, pp. 363-379. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84975089770&partnerID=40&md5=4f646afafdadd3a300ef5daa18e8fc32

DOI: 10.1016/j.ejmech.2016.05.005
AFFILIATIONS: aDipartimento di Farmacia - Scienze Del Farmaco, Università degli Studi di Bari 'A. Moro', via Orabona, 4, Bari, Italy; 
bDepartment of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Smetna 12, Kraków, Poland; 
cFaculty of Chemistry, Jagiellonian University, Ingardena 3, Kraków, Poland; 
dInstitute of Genetics and Biophysics 'Adriano Buzzati Traverso', CNR, Via P. Castellino 111, Naples, Italy; 
eDepartment of Pharmacy, University of Naples Federico II, Via D. Montesano 49, Naples, Italy
ABSTRACT: The 5-HT7 serotonin receptor is revealing a promising target for innovative therapeutic strategies of neurodevelopmental and neuropsychiatric disorders. Here, we report the synthesis of thirty long-chain arylpiperazine analogs of the selective and brain penetrant 5-HT7 receptor agonist LP-211 (1) designed to enhance stability towards microsomal oxidative metabolism. Commonly used medicinal chemistry strategies were used (i.e., reduction of overall lipophilicity, introduction of electron-withdrawing groups, blocking of potential vulnerable sites of metabolism), and in vitro microsomal stability was tested. The data showed that the adopted design strategy does not directly translate into improvements in stability. Instead, the metabolic stability of the compounds was related to the presence of specific substituents in well-defined regions of the molecule. The collected data allowed for the construction of a machine learning model that, in a given chemical space, is able to describe and quantitatively predict the metabolic stability of the compounds. The majority of the synthesized compounds maintained high affinity for 5-HT7 receptors and showed selectivity towards 5-HT6 and dopamine D2 receptors and different selectivity for 5-HT1A and α1 adrenergic receptors. Compound 50 showed 3-fold higher in vitro stability towards oxidative metabolism than 1 and was able to stimulate neurite outgrowth in neuronal primary cultures through the 5-HT7 receptor in a shorter time and at a lower concentration than the agonist 1. A preliminary disposition study in mice revealed that compound 50 was metabolically stable and was able to pass the blood-brain barrier, thus representing a new tool for studying the pharmacotherapeutic potential of 5-HT7 receptor in vivo. © 2016 Elsevier Masson SAS. All rights reserved.
AUTHOR KEYWORDS: 5-HT7 receptor;  Arylpiperazine;  Machine learning;  Microsomal stability;  Neurite outgrowth
DOCUMENT TYPE: Article

SCOPUS news

Vacca, M.a , Tripathi, K.P.b , Speranza, L.a , Aiese Cigliano, R.c , Scalabrì, F.d , Marracino, F.d , Madonna, M.d , Sanseverino, W.c , Perrone-Capano, C.a  e , Guarracino, M.R.b , D'Esposito, M.a  d 
Effects of Mecp2 loss of function in embryonic cortical neurons: A bioinformatics strategy to sort out non-neuronal cells variability from transcriptome profiling
(2016) BMC Bioinformatics, . Article in Press. 
https://www.scopus.com/inward/record.uri?eid=2-s2.0-84954458478&partnerID=40&md5=dc50fc13e2396f6d2c43a5c8b65e54f7
DOI: 10.1186/s12859-015-0859-7
AFFILIATIONS: aInstitute of Genetics and Biophysics A. Buzzati Traverso, National Research Council (CNR)-80131, Naples; 
bLaboratory for Genomics, Transcriptomics and Proteomics (LAB-GTP), High Performance Computing and Networking Institute (ICAR), National Research Council (CNR)-80131, Naples; 
cSequentia Biotech SL, Calle Comte D'Urgell, Barcelona, 240 08036; 
dIRCCS Neuromed, via dell'Elettronica, Pozzilli (Is); 
eDepartment of Pharmacy, University of Naples Federico II, Naples
ABSTRACT: Background: Mecp2 null mice model Rett syndrome (RTT) a human neurological disorder affecting females after apparent normal pre- and peri-natal developmental periods. Neuroanatomical studies in cerebral cortex of RTT mouse models revealed delayed maturation of neuronal morphology and autonomous as well as non-cell autonomous reduction in dendritic complexity of postnatal cortical neurons. However, both morphometric parameters and high-resolution expression profile of cortical neurons at embryonic developmental stage have not yet been studied. Here we address these topics by using embryonic neuronal primary cultures from Mecp2 loss of function mouse model. Results: We show that embryonic primary cortical neurons of Mecp2 null mice display reduced neurite complexity possibly reflecting transcriptional changes. We used RNA-sequencing coupled with a bioinformatics comparative approach to identify and remove the contribution of variable and hard to quantify non-neuronal brain cells present in our in vitro cell cultures. Conclusions: Our results support the need to investigate both Mecp2 morphological as well as molecular effect in neurons since prenatal developmental stage, long time before onset of Rett symptoms. © 2015 Vacca et al.
AUTHOR KEYWORDS: Embryonic cortical neurons;  MeCP2;  Neural cells;  Primary branching;  Rett syndrome;  RNA-sequencing
DOCUMENT TYPE: Article in Press