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Bioorg Med Chem. 2015 Aug 1;23(15):4824-30. doi: 10.1016/j.bmc.2015.05.042. Epub 2015 Jun 1.

Arylpiperazine agonists of the serotonin 5-HT1A receptor preferentially activate cAMP signaling versus recruitment of β-arrestin-2.

Author information

1
Center for Molecular Medicine, Department of Neurology and Clinical Neuroscience, Karolinska Institute and Karolinska University Hospital, 17176 Stockholm, Sweden.
2
Dipartimento di Farmacia-Scienze del Farmaco, Università degli Studi di Bari 'A. Moro', via Orabona, 4, 70125 Bari, Italy.
3
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.

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.

KEYWORDS:

5-HT(1A)R; Functional selectivity; G protein-coupled receptor; Long chain arylpiperazines; cAMP; β-Arrestin-2

PMID:
26081758
DOI:
10.1016/j.bmc.2015.05.042
[Indexed for MEDLINE]

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