NAN-190: an arylpiperazine analog that antagonizes the stimulus effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)

Glennon, Richard A.; Naiman, Noreen; Pierson, M. Edward; Titeler, Milt; Lyon, Robert A.; Weisberg, Ellen

doi:10.1016/0014-2999(88)90212-9

Cited by 178 publications

(105 citation statements)

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“…The drug showing the highest affinity among tested drugs was NAN-190; its subnanomolar affinity is equal to that of a representative a1-adrenoceptor antagonist, prazosin (pKi = 9 -10) (4,25,26). Furthermore, the binding affinity of NAN-190 for a 1-adrenoceptor was not different from that (pKi = 9.2) reported for 5-HT receptors (27), indicating that this drug is an antagonist of not only the 5-HT receptor but also the a1-adrenoceptor.…”

Section: Discussionmentioning

confidence: 72%

Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes

Yoshio

Taniguchi

Itoh

et al. 2001

Japanese Journal of Pharmacology

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ABSTRACT-Binding affinities of serotonin (5-HT)-receptor antagonists and agonists at human recombinant a1-adrenoceptor subtypes (a 1a-, a1b-and a1d-subtypes) were examined and compared with the functional affinities obtained in rat caudal artery (a1A-subtype), dog carotid artery (a1B-subtype) and rat thoracic aorta (=1D-subtype). Most of the 5-HT-receptor antagonists and agonists tested showed relatively high affinity to three a 1-adrenoceptor subtypes. The highest affinity close to 1 nM was seen for in binding and functional studies. 5-Methylurapidil (5-HT1A agonist) and BMY7378 (5-HT1A agonist) showed, respectively, a 1a(a 1A)-or a1d(a1D)-subtype selectivity in both binding and functional affinities, but spiperone (5-HT2A antagonist) showed a1b-selectivity only in binding affinity. Functional affinity of ritanserin (5-HT2A antagonist) to the a1B-subtype was approximately 500-fold lower than that of affinity to the =1b-subtype. The present results show that many 5-HT-receptor antagonists and agonists have high affinity to a1-adrenoceptors, but suggest that there is deviation between their functional affinities and binding affinities for some drugs.Keywords: Serotonin receptor antagonist, Serotonin receptor agonist, a 1-Adrenoceptor, Selectivity a1-Adrenoceptors comprise a heterogeneous family (1 -3). Molecular biological studies have provided evidence for the existence of at least three genes encoding a1a-, a1b-and a1d-adrenoceptors (with lowercase letters) that correspond to the pharmacologically defined native a1A-, a1B-and a 1D-adrenoceptors (with uppercase letters) (4, 5). Pharmacological studies have revealed several subtypeselective agents: for example, 5-methylurapidil, KMD-3213, RS-17053 and nigludipine for the a1a-subtype (6 -9); spiperone for the a1b-subtype (10); and BMY7378 for the a1d-subtype (11, 12). Among them, 5-methylurapidil, spiperone and BMY7378 were originally categorized in serotonin (5-HT) receptor agonists and / or antagonists.Many 5-HT receptor antagonists have been developed and some of them are now clinically used as anticoagulants, antihypertensive drugs and antipsychotic drugs (13,14). Such therapeutic diversity of 5-HT antagonists may be related to their wide spectrum for not only 5-HT receptor family but also for heterogeneous receptors such as dopamine receptors and a1-adrenoceptors (15, 16).The present study was undertaken to examine the possible selectivity for a1-adrenoceptor subtypes of 5-HT receptor agonists and antagonists including clinically active antipsychotic drugs. The selectivity was evaluated with two parameters: binding affinity to recombinant human a 1a-, a1b-and a1d-adrenoceptors expressed in Chinese hamster ovary (CHO) cells and functional affinity to native a1A-(rat caudal artery) (17), a 1B-(dog carotid artery) (18,19) and a 1D-(rat thoracic aorta) (20) adrenoceptors. A good relationship was already reported for a 1-adrenoceptorselective drugs between the recombinant and native a1-adrenoceptors (7, 21). MATERIALS AND METHODS Membrane preparation and radiolig...

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Section: Discussionmentioning

confidence: 72%

Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes

Yoshio

Taniguchi

Itoh

et al. 2001

Japanese Journal of Pharmacology

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“…Spiperone, a compound with appreciable affinity for 5-HTIA, 5-HT2 and dopamine receptors was also effective as an antagonist as was the non-specific 5-HT, receptor ligand methiothepin (Hoyer, 1991). , which is highly specific for 5-HTIA subtype of 5-HT receptors but also has high affinity for a,-adrenoceptor sites (Ki = 0.8 nM ;Glennon et al, 1988), was the most potent antagonist tested.…”

Section: Discussionmentioning

confidence: 99%

Actions of 5‐hydroxytryptamine and 5‐HT_1A receptor ligands on rat dorso‐lateral septal neurones in vitro

Hooff¹,

Galvan²

1992

British J Pharmacology

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1 The actions of 5-hydroxytryptamine (5-HT) and some 5-HTA receptor ligands on neurones in the rat dorso-lateral septal nucleus were recorded in vitro by intracellular recording techniques.2 In the presence of tetrodotoxin (1 tiM) to block any indirect effects, bath application of 30 AM) hyperpolarized the neurones in a concentration-dependent manner and reduced membrane resistance. The hyperpolarization did not exhibit desensitization and was sometimes followed by a small depolarization. 6 The 5-HT2/5-HTlc receptor antagonist, ketanserin (3 jiM) and the 5HT3 receptor antagonist, tropisetron (3 tiM) did not antagonize the 5-HT-induced hyperpolarizations; however, ketanserin blocked the depolarization which sometimes followed the hyperpolarization. 7 It is concluded that the 5-HT-induced membrane hyperpolarization of rat dorso-lateral septal neurones is mediated by 5-HTA receptors.

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“…As a subsequent part of our study on the serotonin 5HTIA and 5HTi A receptors ligands modifications [2-5], we have now investigated the crystal structure of the rigid analog of NAN-190, the well-known postsynaptic 5HTIA receptor antagonist [6]. Introduction of the le,4e-disubstituted cyclohexane system in the place of an aliphatic linked spacer into the ligand molecule diminishes the possibility of a mutual spatial arrangement of terminal fragments which are responsible for a ligand activity towards the investigated receptors.…”

Section: Discussionmentioning

confidence: 99%

Crystal structure of trans-1-(2-methoxyphenyl)-4-[4-(2-phthalimido)cyclohexyl]-piperazine chloride monohydrate, (C25H30N3O3)Cl · H2O

Karolak‐Wojciechowska¹,

Fruziński²,

Paluchowska³

et al. 2002

Zeitschrift Für Kristallographie - New Crystal Structures

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Source of materialThe synthesis of the title compound has been described previously [1] as a part of our research program focused on serotonin 5HTIA receptor ligands. The crystals for X-ray studies were obtained from ethanol: acetone (1:1) mixture by slow evaporation. Experimental detailsThe crystal selected for this study was small and soft, which explains the relative low N(hkl)/N(param) ratio and high /{-values. DiscussionAs a subsequent part of our study on the serotonin 5HTIA and 5HTi A receptors ligands modifications [2-5], we have now investigated the crystal structure of the rigid analog of NAN-190, the well-known postsynaptic 5HTIA receptor antagonist [6]. Introduction of the le,4e-disubstituted cyclohexane system in the place of an aliphatic linked spacer into the ligand molecule diminishes the possibility of a mutual spatial arrangement of terminal fragments which are responsible for a ligand activity towards the investigated receptors. The independent unit of the crystal composed of the protonated main molecule, CP ion, and one water particle. The main molecule under discussion incorporates two border cyclic moieties -arylopiperazine and phthalimide -linked via cyclohexane in chair conformation constituting in fact four carbons atoms spacer. Both cyclic moieties are equatorially located at respective carbons from cyclohexane. The phthalimide fragment is planar and

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NAN-190: an arylpiperazine analog that antagonizes the stimulus effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)

Cited by 178 publications

References 4 publications

Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes

Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes

Actions of 5‐hydroxytryptamine and 5‐HT_1A receptor ligands on rat dorso‐lateral septal neurones in vitro

Crystal structure of trans-1-(2-methoxyphenyl)-4-[4-(2-phthalimido)cyclohexyl]-piperazine chloride monohydrate, (C25H30N3O3)Cl · H2O

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NAN-190: an arylpiperazine analog that antagonizes the stimulus effects of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT)

Cited by 178 publications

References 4 publications

Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes

Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes

Actions of 5‐hydroxytryptamine and 5‐HT1A receptor ligands on rat dorso‐lateral septal neurones in vitro

Crystal structure of trans-1-(2-methoxyphenyl)-4-[4-(2-phthalimido)cyclohexyl]-piperazine chloride monohydrate, (C25H30N3O3)Cl · H2O

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Actions of 5‐hydroxytryptamine and 5‐HT_1A receptor ligands on rat dorso‐lateral septal neurones in vitro