ATIPAMEZOLE


Synonyms	4-(2-ethyl-2-indanyl)imidazole. Antisedan Atipamezole MPV-1248
Status
Molecule Category	UNKNOWN
UNII	03N9U5JAF6
EPA CompTox	DTXSID2049135


Active Pharmaceutical Ingredients Bioactive chemicals	Exact Similarity SubStructure	Threshold (%) >= 70

Structure


InChI Key	HSWPZIDYAHLZDD-UHFFFAOYSA-N
Smiles	CCC1(c2c[nH]cn2)Cc2ccccc2C1
InChI	InChI=1S/C14H16N2/c1-2-14(13-9-15-10-16-13)7-11-5-3-4-6-12(11)8-14/h3-6,9-10H,2,7-8H2,1H3,(H,15,16)

Physicochemical Descriptors

Property Name	Value
Molecular Formula	C14H16N2
Molecular Weight	212.3
AlogP	2.86
Hydrogen Bond Acceptor	1.0
Hydrogen Bond Donor	1.0
Number of Rotational Bond	2.0
Polar Surface Area	28.68
Molecular species	NEUTRAL
Aromatic Rings	2.0
Heavy Atoms	16.0

Reference

Journal : J. Med. Chem.

Title : Potential antidepressants displayed combined alpha(2)-adrenoceptor antagonist and monoamine uptake inhibitor properties.

PubMed ID : 11262089

DOI : 10.1021/jm001040g

Year : 2001

Volume : 44

Issue : 5

First Page : 787

Last Page : 805

Authors : Cordi AA, Berque-Bestel I, Persigand T, Lacoste JM, Newman-Tancredi A, Audinot V, Millan MJ.

Abstract : Classical antidepressants are thought to act by raising monoamine (serotonin and noradrenaline) levels in the brain. This action is generally accomplished either by inhibition of monoamine metabolism (MAO inhibitors) or by blockade of monoamine uptake (tricyclic antidepressants and selective serotonin or noradrenaline reuptake inhibitors). However, all such agents suffer from a time lag (3--6 weeks) before robust clinical efficacy can be demonstrated. This delay may reflect inhibitory actions of noradrenaline at presynaptic alpha(2A)-adrenergic auto- or heteroreceptors which gradually down-regulate upon prolonged exposure. Blockade of presynaptic alpha(2A)-adrenoceptors by an antagonist endowed with monoamine uptake inhibition properties could lead to new antidepressants with greater efficacy and a shorter time lag. In the literature, only two molecules have been described with such a pharmacological profile. Of these, napamezole (2) was chosen as a point of departure for the design of 4(5)-[(3,4-dihydro-2-naphthalenyl)methyl]-4,5-dihydroimidazole (4a), which displayed the desired profile: alpha(2A)-adrenoceptor antagonist properties and serotonin/noradrenaline uptake inhibition. From this original molecule, a series of derivatives was designed and synthesized, encompassing substituted as well as rigid analogues. Structure-activity relationships permitted the selection of 14c (4(5)-[(5-fluoroindan-2-yl)methyl]-4,5-dihydroimidazole) as a development candidate.

Reference

Journal : J. Med. Chem.

Title : Potential antidepressants displayed combined alpha(2)-adrenoceptor antagonist and monoamine uptake inhibitor properties.

PubMed ID : 11262089

DOI : 10.1021/jm001040g

Year : 2001

Volume : 44

Issue : 5

First Page : 787

Last Page : 805

Authors : Cordi AA, Berque-Bestel I, Persigand T, Lacoste JM, Newman-Tancredi A, Audinot V, Millan MJ.

Reference

Journal : J. Med. Chem.

Title : Rigid analogues of the α2-adrenergic blocker atipamezole: small changes, big consequences.

PubMed ID : 20809632

DOI : 10.1021/jm1006269

Year : 2010

Volume : 53

Issue : 19

First Page : 6986

Last Page : 6995

Authors : Vacher B, Funes P, Chopin P, Cussac D, Heusler P, Tourette A, Marien M.

Abstract : We report the discovery of a new family of α(2) adrenergic receptor antagonists derived from atipamezole. Affinities of the compounds at human α(2) and α(1b) receptors as well as their functional activities at hα(2A) receptors were determined in competition binding and G-protein activation assays, respectively. Central α(2) antagonist activities were confirmed in mice after oral administration. Further studies on a selected example: (+)-4-(1a,6-dihydro-1H-cyclopropa[a]inden-6a-yl)-1H-imidazole, (+)-1 (F 14805), were undertaken to probe the potential of the series. On the one hand, (+)-1 increased the release of noradrenaline in mouse frontal cortex following acute systemic administration, the magnitude of this effect being much larger than that obtained with reference agents. On the other, (+)-1 produced minimal cardiovascular effects in intact, anesthetized rat, a surprising outcome that might be explained by its differential action at peripheral and central α(2) receptors. A strategy for improving the therapeutic window of α(2) antagonists is put forward.

Reference

Journal : J. Med. Chem.

Title : Rigid analogues of the α2-adrenergic blocker atipamezole: small changes, big consequences.

PubMed ID : 20809632

DOI : 10.1021/jm1006269

Year : 2010

Volume : 53

Issue : 19

First Page : 6986

Last Page : 6995

Authors : Vacher B, Funes P, Chopin P, Cussac D, Heusler P, Tourette A, Marien M.

Reference

Journal : J. Med. Chem.

Title : Rigid analogues of the α2-adrenergic blocker atipamezole: small changes, big consequences.

PubMed ID : 20809632

DOI : 10.1021/jm1006269

Year : 2010

Volume : 53

Issue : 19

First Page : 6986

Last Page : 6995

Authors : Vacher B, Funes P, Chopin P, Cussac D, Heusler P, Tourette A, Marien M.

Reference

Journal : Bioorg. Med. Chem.

Title : A combined ligand- and structure-based approach for the identification of rilmenidine-derived compounds which synergize the antitumor effects of doxorubicin.

PubMed ID : 27265687

DOI : 10.1016/j.bmc.2016.05.043

Year : 2016

Volume : 24

Issue : 14

First Page : 3174

Last Page : 3183

Authors : Vucicevic J, Srdic-Rajic T, Pieroni M, Laurila JM, Perovic V, Tassini S, Azzali E, Costantino G, Glisic S, Agbaba D, Scheinin M, Nikolic K, Radi M, Veljkovic N.

Abstract : The clonidine-like central antihypertensive agent rilmenidine, which has high affinity for I1-type imidazoline receptors (I1-IR) was recently found to have cytotoxic effects on cultured cancer cell lines. However, due to its pharmacological effects resulting also from α2-adrenoceptor activation, rilmenidine cannot be considered a suitable anticancer drug candidate. Here, we report the identification of novel rilmenidine-derived compounds with anticancer potential and devoid of α2-adrenoceptor effects by means of ligand- and structure-based drug design approaches. Starting from a large virtual library, eleven compounds were selected, synthesized and submitted to biological evaluation. The most active compound 5 exhibited a cytotoxic profile similar to that of rilmenidine, but without appreciable affinity to α2-adrenoceptors. In addition, compound 5 significantly enhanced the apoptotic response to doxorubicin, and may thus represent an important tool for the development of better adjuvant chemotherapeutic strategies for doxorubicin-insensitive cancers.

Assay Description	Organism	Bioactivity
In vitro binding affinity against alpha-2 adrenergic receptor of rat in presence of [3H]-RX 821002 radioligand	None	0.1259 nM
Binding affinity for human alpha-2 adrenergic receptor expressed in CHO cell	Homo sapiens	3.162 nM
Displacement of [3H]-RX821002 from human adrenergic alpha2A receptor expressed in rat C6 cells after 120 mins by liquid scintillation counting	Homo sapiens	1.862 nM
Displacement of [3H]-RX821002 from human adrenergic alpha2B receptor expressed in rat C6 cells after 120 mins by liquid scintillation counting	Homo sapiens	2.239 nM
Displacement of [3H]-RX821002 from human adrenergic Alpha-2C receptor expressed in rat C6 cells after 120 mins by liquid scintillation counting	Homo sapiens	4.169 nM
Displacement of [3H]RS-79948-197 from recombinant human alpha2A adrenoreceptor expressed in CHOK1 cell membrane by scintillation counting method	Homo sapiens	1.2 nM

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Cross References

Resources	Reference
ChEMBL	CHEMBL353972
DrugBank	DB11481
FDA SRS	03N9U5JAF6
PubChem	71310
SureChEMBL	SCHEMBL304971
ZINC	ZINC000005424171

CONTENTS

Structure
Chemical and Physical Properties
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