title: Arylpiperazine agonists of the serotonin 5-HT1A receptor preferentially activate cAMP signaling versus recruitment of β-arrestin-2.
abstract: G protein-coupled receptors (GPCRs) mediate biological signal transduction through complex molecular pathways. Therapeutic effects of GPCR-directed drugs are typically accompanied by unwanted side effects, owing in part to the parallel engagement of multiple signaling mechanisms. The discovery of drugs that are 'functionally selective' towards therapeutic effects, based on their selective control of cellular responses through a given GPCR, is thus a major goal in pharmacology today. In the present study, we show that several arylpiperazine ligands of the serotonin 5-HT1A receptor (5-HT1AR) preferentially activate 3',5'-cyclic adenosine monophosphate (cAMP) signaling versus β-arrestin-2 recruitment. The pharmacology of these compounds is thus qualitatively different from the endogenous agonist serotonin, indicating functional selectivity of 5-HT1AR-mediated response pathways. Preliminary evidence suggests that phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) downstream of 5-HT1AR is a substrate of functionally selective signaling by partial agonists. We propose that the compounds described in the present study are useful starting points for the development of signaling pathway-selective drugs targeting 5-HT1AR.
authors.affiliation: Center for Molecular Medicine, Department of Neurology and Clinical Neuroscience, Karolinska Institute and Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Nikolas
authors.initials: N
authors.lastname: Stroth
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'A. Moro', via Orabona, 4, 70125 Bari, Italy.
authors.forename: Mauro
authors.initials: M
authors.lastname: Niso
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'A. Moro', via Orabona, 4, 70125 Bari, Italy.
authors.forename: Nicola A
authors.initials: NA
authors.lastname: Colabufo
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'A. Moro', via Orabona, 4, 70125 Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Center for Molecular Medicine, Department of Neurology and Clinical Neuroscience, Karolinska Institute and Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Svenningsson
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'A. Moro', via Orabona, 4, 70125 Bari, Italy.
authors.forename: Enza
authors.initials: E
authors.lastname: Lacivita
authors.affiliation: Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'A. Moro', via Orabona, 4, 70125 Bari, Italy. Electronic address: marcello.leopoldo@uniba.it.
authors.forename: Marcello
authors.initials: M
authors.lastname: Leopoldo
mesh_terms: D000818:Animals; D019390:Arrestins / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000494:pharmacology; D044282:Receptor, Serotonin, 5-HT1A / Q000737:chemistry* / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
chemical_list: C000605254:ARRB2 protein, human; D019390:Arrestins; D008024:Ligands; D010879:Piperazines; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D044282:Receptor, Serotonin, 5-HT1A; D000077489:Piperazine; D012701:Serotonin; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3
keywords: 5-HT(1A)R; Functional selectivity; G protein-coupled receptor; Long chain arylpiperazines; cAMP; β-Arrestin-2