Current Perspectives on the Selective Regulation of Dopamine D2 and D3 Receptors

Dong Im Cho,김경만,Mei Zheng 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.10

Among the characterized dopamine receptor subtypes, D2 receptor (D2R) and D3 receptor (D3R) are the main targets of neuroleptics that are currently in use. In particular, D3R is closely related to the etiology of schizophrenia and drug addiction. The spatial expression patterns of D2R and D3R are distinct in certain areas of the brain. D2R are heavily expressed in the regions responsible for motor functions, whereas D3R are more selectively expressed in the limbic regions, which are associated with cognitive and emotional functions. Therefore, disturbances in the motor and endocrine functions, which are the most serious problems caused by the current neuroleptics, are likely to result from the non-selective blockade of D2R. Selective regulation of D3R is needed to separate the desired therapeutic activities from unwanted side effects that result from promiscuous blockade of other receptors. D2R and D3R possess high sequence homology and employ similar signaling pathways, and it is difficult to selectively regulate them. In this review, we discuss the signaling mechanisms, intracellular trafficking, and desensitization properties of D2R and D3R. In addition, the proteins interacting with D2R or D3R are discussed in relation to their roles in the regulation of receptor functions, followed by the current status of the development of selective D3R ligands.

Molecular Co-evolution of Gonadotropin-releasing Hormones and Their Receptors

Seong, Jae-Young,Kwon, Hyuk-Bang The Korean Society for Integrative Biology 2007 Integrative biosciences Vol.11 No.2

Gonadotropin-releasing hormone (GnRH), synthesized in the hypothalamus, plays a pivotal role in the regulation of vertebrate reproduction. Since molecular isoforms of GnRH and their receptors (GnRHR) have been isolated in a broad range of vertebrate species, GnRH and GnRHR provide an excellent model for understanding the molecular co-evolution of a peptide ligand-receptor pair. Vertebrate species possess multiple forms of GnRH, which have been created through evolutionary mechanisms such as gene/chromosome duplication, gene deletion and modification. Similar to GnRHs, GnRH receptors (GnRHR) have also been diversified evolutionarily. Comparative ligand-receptor interaction studies for non-mammalian and mammalian GnRHRs combined with mutational mapping studies of GnRHRs have aided the identification of domains or motifs responsible for ligand binding and receptor activation. Here we discuss the molecular basis of GnRH-GnRHR co-evolution, particularly the structure-function relationship regarding ligand selectivity and signal transduction of mammalian and non-mammalian GnRHRs.

GnRH-II Analogs for Selective Activation and Inhibition of Non-Mammalian and Type-II Mammalian GnRH Receptors

Jae Young Seong,Kaushik Maiti,Jian Hua Li,Ai Fen Wang,Sujata Acharjee,Wang Phil Kim,임욱빈,권혁방 한국분자세포생물학회 2003 Molecules and cells Vol.16 No.2

ecently, we identified three types of non-mammalian gonadotropin-releasing hormone receptors (GnRHR) in the bullfrog (designated bfGnRHR-1-3), and a mammalian type-II GnRHR in green monkey cell lines (denoted gmGnRHR-2). All these receptors responded better to GnRH-II than GnRH-I, while mammalian type-I GnRHR showed greater sensitivity to GnRH-I than GnRH-II. In the present study, we designed new GnRH-II analogs and examined whether they acti- vated or inhibited non-mammalian and mammalian type-II GnRHRs. [D-Ala 6 ]GnRH-II, with D-Ala substi- tuted for Gly 6 in GnRH-II, increased inositol phos- phate (IP) production in cells stably expressing non- mammalian GnRHRs more effectively than native GnRH-II. However, it exhibited lower activity for mammalian type-I GnRHR than GnRH-I itself. Trptorelix-1, a GnRH-II antagonist, inhibited GnRH- induced IP production in cells expressing non- mammalian GnRHRs more effectively than Cetrorelix, a GnRH-I antagonist. Trptorelix-1, however, had lower potency for mammalian type-I GnRHR than Cetrorelix. Ligand-receptor binding assays revealed that [D-Ala 6 ]GnRH-II and Trptorelix-1 have higher affinities for non-mammalian GnRHRs but lower af- finities for mammalian type-I GnRHR than GnRH-II and Cetrorelix, respectively. Moreover, [D-Ala 6 ]GnRH- II and Trptorelix-1 had a higher affinity for gmGnRHR-2 than GnRH-II and Cetrorelix, respec- tively. These results indicate that [D-Ala 6 ]GnRH-II and Trptorelix-1 are highly effective agonist and antagonist, respectively, for non-mammalian and type- II mammalian GnRHRs

$Tyr^1$ and $Ile^7$ of Glucose-Dependent Insulinotropic Polypeptide (GIP) Confer Differential Ligand Selectivity toward GIP and Glucagon-like Peptide-1 Receptors

Moon, Mi-Jin,Kim, Hee-Young,Kim, Sin-Gon,Park, Ju-Ri,Choi, Dong-Seop,Hwang, Jong-Ik,Seong, Jae-Young Korean Society for Molecular and Cellular Biology 2010 Molecules and cells Vol.30 No.2

Glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released in response to food intake and potentiate insulin secretion from pancreatic ${\beta}$ cells through their distinct yet related G protein-coupled receptors, GLP1R and GIPR. While GLP-1 and GIP exhibit similarity in their N-terminal sequence and overall ${\alpha}$-helical structure, GLP-1 does not bind to GIPR and vice versa. To determine which amino acid residues of these peptide ligands are responsible for specific interaction with their respective receptors, we generated mutant GIP in which several GLP-1-specific amino acid residues were substituted for the original amino acids. The potency of the mutant ligands was examined using HEK293 cells transfected with GLP1R or GIPR expression plasmids together with a cAMP-responsive element-driven luciferase (CRE-luc) reporter plasmid. A mutated GIP peptide in which $Tyr^1$, $Ile^7$, $Asp^{15}$, and $His^{18}$ were replaced by His, Thr, Glu, and Ala, respectively, was able to activate both GLP1R and GIPR with moderate potency. Replacing the original $Tyr^1$ and/or $Ile^7$ in the Nterminal moiety of this mutant peptide allowed full activation of GIPR but not of GLP1R. However, reintroducing $Asp^{15}$ and/or $His^{18}$ in the central ${\alpha}$-helical region did not significantly alter the ligand potency. These results suggest that Tyr/$His^1$ and Ile/$Thr^7$ of GIP/GLP-1 peptides confer differential ligand selectivity toward GIPR and GLP1R.

Tyr1 and Ile7 of Glucose-Dependent Insulinotropic Polypeptide (GIP) Confer Differential Ligand Selectivity toward GIP and Glucagon-like Peptide-1 Receptors

문미진,Hee Young Kim,김신곤,Juri Park,최동섭,황종익,성재영 한국분자세포생물학회 2010 Molecules and cells Vol.30 No.2

Glucagon like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are incretin hormones released in response to food intake and potentiate insulin secretion from pancreatic β cells through their distinct yet related G protein-coupled receptors, GLP1R and GIPR. While GLP-1 and GIP exhibit similarity in their N-terminal sequence and overall α-helical structure, GLP-1 does not bind to GIPR and vice versa. To determine which amino acid residues of these peptide ligands are responsible for specific interaction with their respective receptors, we generated mutant GIP in which several GLP-1-specific amino acid residues were substituted for the original amino acids. The potency of the mutant ligands was examined using HEK293 cells transfected with GLP1R or GIPR expression plasmids together with a cAMP-responsive element-driven luciferase (CRE-luc) reporter plasmid. A mutated GIP peptide in which Tyr1, Ile7, Asp15, and His18were replaced by His, Thr, Glu, and Ala, respectively, was able to activate both GLP1R and GIPR with moderate potency. Replacing the original Tyr1 and/or Ile7 in the Nterminal moiety of this mutant peptide allowed full activation of GIPR but not of GLP1R. However, reintroducing Asp15 and/or His18 in the central α-helical region did not significantly alter the ligand potency. These results suggest that Tyr/His1 and Ile/Thr7 of GIP/GLP-1 peptides confer differential ligand selectivity toward GIPR and GLP1R.

Preparation and characterization of an organic/inorganic hybrid sorbent (PLE) to enhance selectivity for As(V)

An, Byungryul,Kim, Hakchan,Park, Chanhyuk,Lee, Sang-Hyup,Choi, Jae-Woo Elsevier 2015 Journal of hazardous materials Vol.289 No.-

<P><B>ABSTRACT</B></P> <P>For the selective removal of arsenate (As(V)) a hybrid sorbent was prepared using a non-toxic natural organic material, chitosan, by loading a transition metal, nickel. The immobilization of nickel was achieved by coordination with a deprotonated amino group (NH<SUB>2</SUB>) in the chitosan polymer chain. The amount of nickel was directly correlated to the presence of the amino group and was calculated to be 62mg/g. FTIR spectra showed a peak shift from 1656 to 1637cm<SUP>−1</SUP> after Ni<SUP>2+</SUP> loading, indicating the complexation between the amino group and nickel, and a peak of As(V) was observed at 834cm<SUP>−1</SUP>. An increase of sulfate concentration from 100mg/L to 200mg/L did not significantly affect As(V) sorption, and an increase in the concentration of bicarbonate reduced the As(V) uptake by 33%. The optimal pH of the solution was determined at pH 10, which is in accordance with the fraction of HAsO<SUB>4</SUB> <SUP>2−</SUP> and AsO<SUB>4</SUB> <SUP>−3</SUP>. According to a fixed column test, a break through behavior of As(V) revealed that selectivity for As(V) was over sulfate. Regeneration using 5% NaCl extended the use of sorbent to up to uses without big loss of sorption capacity.</P> <P><B>Highlights</B></P> <P> <UL> <LI> A natural biopolymer, chitosan, was used to selectively remove As(V). </LI> <LI> A deprotonated amino group was coordinated with nickel by LAB. </LI> <LI> Immobilized nickel played a key role in the selective removal of As(V) over SO<SUB>4</SUB> <SUP>2−</SUP>. </LI> <LI> The breakthrough sequence is followed: As(V)>SO<SUB>4</SUB> <SUP>2−</SUP> >HCO<SUB>3</SUB> <SUP>−</SUP> >NO<SUB>3</SUB> <SUP>−</SUP> >Cl<SUP>−</SUP>. </LI> <LI> The PLE is reused without a significant loss of As(V) uptake up to 10 times. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Synthesis of oxidative metabolites of CRA13 and their analogs: Identification of CRA13 active metabolites and analogs thereof with selective CB₂R affinity

Hassan, Ahmed H.E.,Cho, Min Chang,Kim, Hye In,Yang, Ji Seul,Park, Kyung Tae,Hwang, Ji Young,Jang, Choon-Gon,Park, Ki Duk,Lee, Yong Sup Elsevier 2018 Bioorganic & medicinal chemistry Vol.26 No.18

<P><B>Abstract</B></P> <P>CRA13; a peripheral dual CB<SUB>1</SUB>R/CB<SUB>2</SUB>R agonist with clinically proven analgesic properties, infiltrates into CNS producing adverse effects due to central CB<SUB>1</SUB>R agonism. Such adverse effects might be circumvented by less lipophilic compounds with attenuated CB<SUB>1</SUB>R affinity. Metabolism produces less lipophilic metabolites that might be active metabolites. Some CRA13 oxidative metabolites and their analogues were synthesized as less lipophilic CRA13 analogues. Probing their CB<SUB>1</SUB>R and CB<SUB>2</SUB>R activity revealed the alcohol metabolite <B>8c</B> as a more potent and more effective CB<SUB>2</SUB>R ligand with attenuated CB<SUB>1</SUB>R affinity relative to CRA13. Also, the alcohol analogue <B>8b</B> and methyl ester <B>12a</B> possessed enhanced CB<SUB>2</SUB>R affinity and reduced CB<SUB>1</SUB>R affinity. The CB<SUB>2</SUB>R binding affinity of alcohol analogue <B>8b</B> was similar to CRA13 while that of methyl ester <B>12a</B> was more potent. <I>In silico</I> study provided insights into the possible molecular interactions that might explain the difference in the elicited biological activity of these compounds.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Design rational based on active metabolite approach. </LI> <LI> Alcoholic, carboxylic metabolites of CRA13 and their analogs were synthesized and evaluated. </LI> <LI> Evaluated compounds were more selective towards CB<SUB>2</SUB>R. </LI> <LI> Compound <B>8c</B> was more potent than CRA13 as CB<SUB>2</SUB>R ligand with attenuated CB<SUB>1</SUB>R affinity. </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Design, synthesis, and biological evaluation of cyclopropyl analogues of stilbene with raloxifene side chain as subtypeselective ligands for estrogen receptor

Hye Lim Yeo,송윤선,류재하,김희두 대한약학회 2013 Archives of Pharmacal Research Vol.36 No.9

We have designed the cyclopropane analog ofstilbene as subtype-selective ligands for estrogen receptorbased on the bioisosterism that cyclopropane could act asalkene bioisoster. Three cyclopropane analogs were preparedefficiently starting from 4-benzyloxybenzaldehyde,and evaluated for their binding to estrogen receptors ERaand ERb. These cyclopropane analogs were also found tobe full agonists in estrogen receptor-mediated gene transcriptionassay. Compared to the stilbene analogs such astamoxifen and raloxifene, the three cyclopropane analogsshowed lower binding affinity for estrogen receptor, buthigher subtype selectivity for ERa. The structure–activityrelationship revealed from this study might provide cluesfor improving subtype selectivity for ERa.

Distinct evolution of toll‑like receptor signaling pathway genes in cetaceans

Ran Tian,Inge Seim,Zepeng Zhang,Ying Yang,Wenhua Ren,Shixia Xu,Guang Yang 한국유전학회 2019 Genes & Genomics Vol.41 No.12

Background The relatively rapid spread and diversity of marine pathogens posed an initial and ongoing challenge for cetaceans (whales, dolphins, and porpoises), descendants of terrestrial mammals that transitioned from land to sea approximately 56 million years ago. Toll-like receptors (TLRs) play important roles in regulating immunity against pathogen infections by detecting specific molecular patterns and activating a wide range of downstream signaling pathways. The ever-increasing catalogue of mammalian genomes offers unprecedented opportunities to reveal genetic changes associated with evolutionary and ecological processes. Objective This study aimed to explore the molecular evolution of TLR signaling pathway genes in cetaceans. Methods Genes involved in the TLR signaling pathway were retrieved by BLAST searches using human coding sequences as queries. We tested each gene for positive selection along the cetacean branches using PAML and Hyphy. Physicochemical property changes of amino acids at all positively selected residues were assessed by TreeSAAP and visualized with WebLogo. Bovine and dolphin TLR4 was assessed using human embryonic kidney cell line HEK293, which lacks TLR4 and its co-receptor MD-2. Results We demonstrate that eight TLR signaling pathway genes are under positive selection in cetaceans. These include key genes in the response to Gram-negative bacteria: TLR4, CD14, and LY96 (MD-2). Moreover, 41 out of 65 positively selected sites were inferred to harbor substitution that dramatically changes the physicochemical properties of amino acids, with most of them situated in or adjacent to functional regions. We also found strong evidence that positive selection occurred in the lineage of the Yangtze finless porpoise, likely reflecting relatively recent adaptions to a freshwater milieu. Species-specific differences in TLR4 response were observed between cetacean and terrestrial species. Cetacean TLR4 was significantly less responsive to lipopolysaccharides from a terrestrial E. coli strain, possibly a reflection of the arms race of host–pathogen co-evolution faced by cetaceans in an aquatic environment. Conclusion This study provides further impetus for studies on the evolution and function of the cetacean immune system.

Lariat Azacrown Ether를 포함하는 액체막을 이용한 알칼리 및 알칼리토 금속 이온의 분리

최규성 ( Kyu Seong Choi ) 경남대학교 환경문제연구소 2001 환경연구 Vol.24 No.-