Dopamine D3 receptor selective ligands with varying intrinsic efficacies at adenylyl cyclase inhibition and mitogenic signaling pathways.

Synapse
Michelle TaylorRobert R Luedtke

Abstract

A panel of structurally related substituted 4-phenylpiperazines with nanomolar affinity and selectivity at D3 dopamine receptors has been synthesized. Compounds in which a heterocyclic (2-phenyl pyridyl, 3-phenyl pyridyl, benzothiophene, or benzofuran) moiety is adjacent to the amide was varied and/or a double bond (trans-butenyl) replaced the four-carbon aliphatic chain linking the arylamide with the 4-phenylpiperazine moiety were compared for (a) affinity at human D2 and D3 dopamine receptors, (b) intrinsic efficacy using an adenylyl cyclase inhibition assay, and (c) intrinsic efficacy using a mitogenic assay. All 16 compounds were (a) more efficacious for the D3 receptor cyclase inhibition assay than for the D3 receptor mitogenic assay and (b) exhibited the same or greater efficacy at D3 compared to D2 receptor (with the exception of one compound). Although the heterocyclic amide moiety appears to be the pivotal structural element determining the intrinsic efficacy of our D3 receptor selective compounds, the magnitude of the efficacy is modulated by the (a) substituent(s) on the phenyl piperazine and (b) the saturation of the four-carbon chain that links the arylamide and the phenylpiperazine. In addition, our ligands are fu...Continue Reading

References

Mar 1, 1991·Clinical Endocrinology·D Cunnah, M Besser
Apr 1, 1974·Analytical Biochemistry·Y SalomonM Rodbell
Jan 1, 1993·International Review of Neurobiology·D R SibleyY Shen
Sep 1, 1997·Molecular Pharmacology·S W Robinson, M G Caron
Nov 5, 1997·Advances in Pharmacology·R M HuffL V Goodman
Nov 5, 1997·Advances in Pharmacology·G R UhlN Takahashi
Feb 11, 1998·Physiological Reviews·C MissaleM G Caron
Aug 15, 1998·Trends in Pharmacological Sciences·W P Clarke, R A Bond
Jan 16, 1999·Molecular and Cellular Neurosciences·E V KuzhikandathilG S Oxford
Feb 2, 2000·Neuroscience and Biobehavioral Reviews·D ValloneE Borrelli
Oct 29, 2000·Trends in Neurosciences·S C Sealfon, C W Olanow
Dec 13, 2000·Pharmacology, Biochemistry, and Behavior·J J Canales, S D Iversen
Jun 27, 2002·Trends in Pharmacological Sciences·Terry Kenakin, Ongun Onaran
Jul 20, 2002·Progress in Neurobiology·André Nieoullon
Jun 12, 2003·Bioorganic & Medicinal Chemistry Letters·Amy Hauck NewmanRobert R Luedtke
Jul 23, 2003·Trends in Pharmacological Sciences·Terry Kenakin
Nov 8, 2003·Molecular and Cellular Endocrinology·Susan E Senogles
Dec 4, 2003·Progress in Neuro-psychopharmacology & Biological Psychiatry·Shitij Kapur, David Mamo
May 4, 2004·Molecular and Cellular Neurosciences·Eldo V KuzhikandathilJennifer Pasuit
Nov 4, 2004·Journal of Receptor and Signal Transduction Research·Kim A NeveHeather Trantham-Davidson
Dec 8, 2004·Bioorganic & Medicinal Chemistry·Wenhua ChuRobert H Mach
Jan 20, 2005·Proceedings of the National Academy of Sciences of the United States of America·Bruce E CohenLily Y Jan
Mar 24, 2005·Molecular Pharmacology·William P Clarke
May 27, 2005·Journal of Medicinal Chemistry·Amy Hauck NewmanMichael A Nader
Oct 6, 2005·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Zheng-Xiong XiEliot L Gardner
Nov 18, 2005·Bioorganic & Medicinal Chemistry·Suwanna VangveravongRobert H Mach
Jun 29, 2006·The Journal of Pharmacology and Experimental Therapeutics·Jonathan D UrbanRichard B Mailman
Apr 3, 2007·Trends in Neurosciences·M Angela Cenci
Oct 10, 2007·The Journal of Biological Chemistry·Agustin ZapataToni S Shippenberg

❮ Previous
Next ❯

Citations

Feb 26, 2011·Journal of Medicinal Chemistry·Zhude TuRobert H Mach
May 29, 2012·Journal of Medicinal Chemistry·Amy Hauck NewmanLei Shi
Feb 4, 2011·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·B L BlaylockM A Nader
May 4, 2011·Bioorganic & Medicinal Chemistry·Suwanna VangveravongRobert H Mach
May 3, 2016·Expert Opinion on Drug Discovery·Antoni CortésVicent Casadó
Jun 28, 2016·Pharmacology & Therapeutics·Gian Marco LeggioFilippo Drago
Jan 16, 2020·European Journal of Medicinal Chemistry·Mariarosaria FerraroGiovanni Bottegoni
Jun 3, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Boeun LeeRobert R Luedtke
Aug 14, 2020·ACS Chemical Neuroscience·Hamed S Hayatshahi, Jin Liu

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.