A new chemotype inhibitor for the human organic cation transporter 3 (hOCT3). Issue 18 (15th September 2017)

• Record Type: Journal Article
• Authors: Pan, Xiaolei; Iyer, Kavita A.; Liu, Hebing; Sweet, Douglas H.; Dukat, Małgorzata
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 18(2017)
• Page Start: 4440
• Page End: 4445
• Publication Date: 2017-09-15
• Subjects: OCT3 -- Phenylguanidines -- 3D homology model -- In vitro studies -- SAR; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2017.08.008
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Human organic cation transporters (OCTs) represent an understudied neurotransmitter uptake mechanism for which no selective agents have yet been identified. Several neurotransmitters (e.g. serotonin, norepinephrine) are low-affinity substrates for these transporters, but possess higher affinity for other transporters (e.g. the serotonin or norepinephrine transporters; SERT and NET, respectively). We have identified a new class of OCT inhibitors with a phenylguanidine structural scaffold. Here, we examine the actions of a series of such compounds and report preliminary structure–activity relationships (SARs) – the first dedicated SAR study of OCT3 action. Initial results showed that the presence of a substituent on the phenyl ring, as well as its position, contributes to the phenylguanidines' inhibitory potency (IC50 values ranging from 2.2 to >450 μM) at hOCT3. There is a trend towards enhanced inhibitory potency of phenylguanidines with increased lipophilic character and the size of the substituent at the phenyl 4-position, with the latter reaching a ceiling effect. The first PiPT-based hOCT3 homology models were generated and are in agreement with our biological data.