Octopaminergic agonists for the cockroach neuronal octopamine receptor

摘要

The compounds 1-(2,6-diethylphenyl)imidazolidine-2-thione and 2-(2,6-diethylphenyl)imidazolidine showed the almost same activity as octopamine in stimulating adenylate cyclase of cockroach thoracic nervous system among 70 octopamine agonists, suggesting that only these compounds are full octopamine agonists and other compounds are partial octopamine agonists. The quantitative structure-activity relationship of a set of 22 octopamine agonists against receptor 2 in cockroach nervous tissue, was analyzed using receptor surface modeling. Three-dimensional energetics descriptors were calculated from receptor surface model/ligand interaction and these three-dimensional descriptors were used in quantitative structure-activity relationship analysis. A receptor surface model was generated using some subset of the most active structures and the results provided useful information in the characterization and differentiation of octopaminergic receptor.

>Abbreviation:

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AEA

arylethanolamine

AII

2-(arylimino)imidazolidine

AIO

2-(arylimino)oxazolidine

AIT

2-(arylimino)thiazolidine

APAT

2-(α-phenylethylamino)-2-thiazoline

BPAT

2-(β-phenylethylamino)-2-thiazoline

CAO

2-(3-chlorobenzylamino)-2-oxazoline

DCAO

2-(3,5-dichlorobenzylamino)-2-oxazoline

DET5

2-(2,6-diethylphenylimino)-5-methylthiazolidine

DET6

2-(2,6-diethylphenylimino)thiazine

EGTA

ethylene glycol bis(β-aminoethyl ether)-N,N,N′,N′-tetraacetic acid

GFA

genetic function approximation

G/PLS

genetic partial least squares

IND

2-aminomethyl-2-indanol

LAH

lithium aluminum hydride

MCSG

maximum common subgroup

MCT6

2-(2-methyl-4-chlorophenylimino)thiazine

OA

octopamine

PLS

partial least squares

QSAR

quantitative structure-activity relationship

SBAT

2-(substituted benzylamino)-2-thiazoline

SD

the sum of squared deviations of the dependent variable values from their mean

SPIT

3-(substituted phenyl)imidazolidine-2-thione

THI

2-amino-1-(2-thiazoyl)ethanol

TMS

tetramethyl silane

class="kwd-title">Keywords: Periplaneta americana, receptor surface model, cerius2, octopamine agonist class="head no_bottom_margin" id="s1title" style="text-transform: uppercase;">IntroductionOctopamine [2-amino-1-(4-hydroxyphenyl)ethanol] which has been found to be present in high concentrations in various insect tissues, is the monohydroxyllic analogue of the vertebrate hormone noradrenalin. Octopamine was first discovered in the salivary glands of the octopus by . It has been found that octopamine is present at a high concentrations in various invertebrate tissues (). This multifunctional and naturally occurring biogenic amine has been well studied and established as 1) a neurotransmitter, controlling the firefly light organ and endocrine gland activity in other insects; 2) a neurohormone, inducing mobilization of lipids and carbohydrates; 3) a neuromodulator, acting peripherally on muscles, fat body, corpora cardiaca and the corpora allata, and 4) a centrally acting neuromodulator, influencing motor patterns, habituation and even memory in various invertebrate species (, ). The action of octopamine is mediated through various receptor classes. Three different receptor classes OAR1, OAR2A and OAR2B have been distinguished from non-neuronal tissues (). OAR2 is coupled to G-proteins and is specifically linked to an adenylate cyclase. Thus, the physiological actions of OAR2 have been shown to be associated with elevated levels of cAMP (). In the nervous system of the locust, Locusta migratoria, a particular receptor class was characterized and established as a new class OAR3 by pharmacological investigations of the [³H]OA binding site using various agonists and antagonists (, , ; ; ).Recently much attention has been directed at the octopamine agonist as a valid target in the development of safer and selective pesticides (; ; ). Structure-activity studies of various types of octopamine agonists and antagonists were also reported using the nervous tissue of the migratory locust, L. migratoria (, , href="#i1536-2442-003-10-0001-roeder3" rid="i1536-2442-003-10-0001-roeder3" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_96699086">1995; href="#i1536-2442-003-10-0001-roeder4" rid="i1536-2442-003-10-0001-roeder4" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_96699083">Roeder and Gewecke, 1990; href="#i1536-2442-003-10-0001-roeder5" rid="i1536-2442-003-10-0001-roeder5" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_96699094">Roeder and Nathanson, 1993). However, information on the structural requirements of these octopamine agonists and antagonists for high octopamine-receptor ligands is still limited. It is therefore of critical importance to provide information on the pharmacological properties of octopamine receptor types and subtypes. Our interest in octopaminergic agonists was aroused by the results of quantitative structure-activity relationship (QSAR) studies using various physicochemical parameters as descriptors (href="#i1536-2442-003-10-0001-hirashima12" rid="i1536-2442-003-10-0001-hirashima12" class=" bibr popnode">Hirashima et al., 1999a; href="#i1536-2442-003-10-0001-pan2" rid="i1536-2442-003-10-0001-pan2" class=" bibr popnode">Pan et al., 1997a) and receptor surface modeling (href="#i1536-2442-003-10-0001-hirashima9" rid="i1536-2442-003-10-0001-hirashima9" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_328530610">Hirashima et al., 1998a). Furthermore, molecular modeling and conformational analyses were performed in Catalyst/Hypo to gain a better understanding of the interactions between octopaminergic antagonists and OAR3 in order to determine the conformations required for binding activity (href="#i1536-2442-003-10-0001-pan1" rid="i1536-2442-003-10-0001-pan1" class=" bibr popnode">Pan et al., 1997b). A similar procedure was repeated using octopamine agonists (href="#i1536-2442-003-10-0001-hirashima7" rid="i1536-2442-003-10-0001-hirashima7" class=" bibr popnode tag_hotlink tag_tooltip" id="__tag_328530614">Hirashima et al., 1999b). However, binding activity is not enough for evaluating octopamine-agonist activity, because it is difficult to determine the different activities of octopamine agonists and antagonists. In drug discovery, it is common to have measured activity data for a set of compounds acting upon a particular protein but not to have knowledge of the three-dimensional structure of the protein active site. In the absence of such three-dimensional information, one can attempt to build a hypothetical model of the receptor site that can provide insight about receptor site characteristics. Such a model is known as a receptor surface model, which provides compact and quantitative descriptors that capture three-dimensional information about a putative receptor site. Thus, the current work is aimed to perform 3D receptor surface modeling on a set of octopamine agonists using the thoracic nervous system of the American cockroach, Periplaneta americana, in which octopamine-agonist action is thought to be due to cAMP elevation at OAR2 (href="#i1536-2442-003-10-0001-hirashima14" rid="i1536-2442-003-10-0001-hirashima14" class=" bibr popnode">Hirashima et al., 1992).