Atropisomeric Derivatives of 2‘,6‘-Disubstituted (<i>R</i>)-11-Phenylaporphine:  Selective Serotonin 5-HT<sub>7</sub> Receptor Antagonists

Linnanen, Tero; Brisander, Magnus; Unelius, Lena; Rosqvist, Susanne; Nordvall, Gunnar; Hacksell, Uli; Johansson, Anette M.

doi:10.1021/jm0108505

Cited by 37 publications

(42 citation statements)

References 17 publications

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“…The pharmacological profile of various aporphine derivatives (73), as leads for highly selective 5-HT 7 receptor ligands, was reported recently by Linnanen et al [84][85][86]. Preliminary SAR studies indicate that a C11-phenyl group is beneficial for the interaction of (R)-aporphines with both the 5-HT 1A and the 5-HT 7 receptor subtypes.…”

Section: Emerging 5-ht 7 Receptor Antagonistsmentioning

confidence: 83%

“…The atropisomeric (6aR,aR)-75 showed the same selectivity for 5-HT 7 receptors as (6aR,aS)-75 but was ∼ 5 times less potent (K i = 20.8 nM). The atropisomer (6aR,aS)-75 exhibited 5-HT 7 antagonism in a cAMP assay without evidence of inverse agonist action [84][85][86]. Researchers at American Home Products Corp. (now Wyeth Phamaceuticals) disclosed a patent application covering novel pyrrolo-isoquinoline and tetrahydropyrroloisoquinoline derivatives, represented by the general chemical structure 76, for the treatment of diseases associated with 5-HT 7 receptor disfunction.…”

Section: Emerging 5-ht 7 Receptor Antagonistsmentioning

confidence: 99%

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Recent progress in 5-HT₇receptors: potential treatment of central and peripheral nervous system diseases

Slassi¹,

Isaac²,

Tao³

2004

Expert Opinion on Therapeutic Patents

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In light of the barrage of recent reviews on 5-HT 7 receptor agonists and antagonists, this article will highlight and review the research advances published in the patent literature between January 1997 and December 2003. The article is supplemented with selected references on the design, synthesis and development of novel 5-HT 7 agents to treat central and peripheral nervous system diseases. Emphasis is placed on recent advances in the possible involvement of 5-HT 7 serotonergic agents in the treatment of learning and memory, depression, schizophrenia and migraine. By no means has any attempt been made to exhaustively review the literature, but rather, primary references together with citations to recent literature reviews have been included in each section.

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Section: Emerging 5-ht 7 Receptor Antagonistsmentioning

confidence: 83%

Section: Emerging 5-ht 7 Receptor Antagonistsmentioning

confidence: 99%

Recent progress in 5-HT₇receptors: potential treatment of central and peripheral nervous system diseases

Slassi¹,

Isaac²,

Tao³

2004

Expert Opinion on Therapeutic Patents

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“…Thus, renders it as a novel drug target to cure such ailments. Only a few compounds have been reported, in recent years, as antagonists [13][14][15][16][17][18] , selective agonists 15,19 , nonselective agonists 20,21 and partial agonists 15,19,22 at the 5-HT7 receptor. However, the use of some of the potent compounds was limited due to strong side effects such as blood pressure and heart rate changes 20 or poor experimental metabolic stability.…”

Section: Introductionmentioning

confidence: 99%

Cp-MLR Directed Qsar Rationales for the Activity Profile of (Phenylpiperazinyl-Alkyl) Oxindoles as 5-Ht7 Receptor Ligands

Choudhary¹,

Sharma²

2015

Int. J. Res. Ayurveda Pharm.

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The 5-HT7 receptor binding affinities of the oxindole derivatives have been quantitatively analyzed in terms of Dragon descriptors. The derived QSAR models have provided rationales to explain the binding affinity of titled compounds. In order to improve the 5-HT7 receptor binding affinity of a compound higher value of molecular topology and symmetry accounting parameter path/walk 2-Randic shape index (descriptor PW2) and lower value of eigenvector coefficient sum from adjacency matrix (descriptor VEA1) are favorable. Presence of more number of sp 3 hybridized secondary carbon atoms (descriptor nCs) and secondary aliphatic amides (descriptor nCONHR) in a molecule will be supportive to the activity. The associations of masses to the eigenvalue n.4 of Burden matrix (BEHm4), van der Waals volume to path length 2 of Geary autocorrelation (GATS2v) and Sanderson electronegativity to path length 6 of Moran autocorrelation (MATS6e) and path length 4 of Geary autocorrelation (GATS4e) have shown the prevalence of atomic properties and charge content in terms of 9 th and 5 th order topological and mean topological charge indices (GGI9 and JGI5) to explain the binding affinity. The PLS analysis has also confirmed the dominance of information content of the CP-MLR identified descriptors. The derived models and participating descriptors in them have suggested that the substituents of oxindole moiety have sufficient scope for further modification.

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“…A afinidade razoável do derivado 71 para receptores 5-HT 7 indicou a possibilidade de se gerar novos ligantes deste receptor, potentes e seletivos, através da modificação molecular da estrutura quími-ca do protótipo, variando-se o padrão de substituição no anel fenila ligado em C-11 74 . Trabalhos anteriores indicaram que a introdução de um grupo fenila em C-11 favorece a interação de (R)-aporfinas funcionalizadas com ambos os receptores serotoninérgicos dos subtipos 5-HT 1A e 5-HT 7 75 .…”

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“…O perfil destes derivados pode, entretanto, ser modificado pela introdução, simétrica ou não simétrica, de substituintes nas posições orto da fenila ligada em C-11 no esqueleto aporfínico. A afinidade dos derivados simetricamente substituídos pelos receptores D 2A , 5-HT 1A e 5-HT 7 foi diminuída com exceção do derivado dimetoxi 72a, que mostrou ser o análogo mais seletivo e potente 74 76 .…”

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Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

Santos¹,

Pinheiro²,

Sodero³

et al. 2007

Quím. Nova

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Recebido em 26/9/05; aceito em 30/3/06; publicado na web em 26/9/06 ATROPISOMERISM: THE EFFECT OF THE AXIAL CHIRALITY IN BIOACTIVE COMPOUNDS. Atropisomerism is a special kind of stereoisomeric relationship that arises from the freezing of a certain conformation of an organic molecule, associated with a high rotational barrier about a single covalent bond. Atropisomerism has been originally described in orto-functionalyzed biphenyl derivatives, but a lot of other organic functionalities can present this structural phenomenon, characterized by the presence of chiral properties in compounds that don't present classical stereogenic centers. Atropisomeric compounds, intermediates and catalysts have well-know importance in organic synthesis, but the influence of the axial chirality in substances able to modulate biological systems is still not very exploited in drug design and development. In this context, the present account describes the importance of this structural property in the medicinal chemistry of different classes of bioactive compounds or therapeutic agents, emphasizing how atropisomerism could affect the molecular recognition of a ligand or a prototype by the target bioreceptor.Keywords: atropisomerism; atropisomerism of drugs; stereoselective molecular recognition. INTRODUÇÃOO fenômeno conhecido como atropoisomerismo, denominação oriunda da palavra grega atropos (i.e. sem rotação), é atribuído a um tipo de estereoisomerismo característico de sistemas onde a rotação livre em torno de uma ligação simples é impedida, produzindo uma barreira energética suficientemente elevada, de modo a permitir o isolamento ou simplesmente a detecção dos diferentes rotâmeros, chamados atropoisômeros 1,2 . Este tipo de isomeria axial é caracterizada pela atividade ótica promovida por um eixo de ligação, não necessitando que a substância apresente carbono estereogênico como elemento de quiralidade. O fenômeno foi observado pela primeira vez por Christie e Kenner 3 , após a resolução dos atropoisômeros do ácido 6,6'-dinitro-2,2'-difênico 1, os quais não se mostraram interconversíveis à temperatura ambiente (Figura 1).A nomenclatura de substâncias que apresentam quiralidade axial pode ser atribuída como R ou S pela aplicação das regras de prioridade de Cahn-Ingold-Prelog 4,5 , conforme exemplificado na Figura 2. A partir da projeção da estrutura vista na direção do eixo de ligação do sistema bifenílico, deve-se definir a ordem de prioridade dos grupos funcionais, iniciando por aqueles mais próximos ao observador e, em seguida, atribuir a configuração absoluta R ou S com base no sentido da rotação produzida quando se caminha do substituinte de maior prioridade para o de menor prioridade. Apesar de ser opcional, a descrição da configuração absoluta de estereoisômeros atropoisoméricos deve ser acompanhada pela introdução do prefixo a, i.e. aR ou aS, visando distinguí-los de outros tipos de compostos oticamente ativos. De maneira alternativa, os compostos atropoisoméricos podem ser vistos como hélices e suas configurações descritas...

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Atropisomeric Derivatives of 2‘,6‘-Disubstituted (R)-11-Phenylaporphine: Selective Serotonin 5-HT₇ Receptor Antagonists

Cited by 37 publications

References 17 publications

Recent progress in 5-HT₇receptors: potential treatment of central and peripheral nervous system diseases

Recent progress in 5-HT₇receptors: potential treatment of central and peripheral nervous system diseases

Cp-MLR Directed Qsar Rationales for the Activity Profile of (Phenylpiperazinyl-Alkyl) Oxindoles as 5-Ht7 Receptor Ligands

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

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Atropisomeric Derivatives of 2‘,6‘-Disubstituted (R)-11-Phenylaporphine: Selective Serotonin 5-HT7 Receptor Antagonists

Cited by 37 publications

References 17 publications

Recent progress in 5-HT7receptors: potential treatment of central and peripheral nervous system diseases

Recent progress in 5-HT7receptors: potential treatment of central and peripheral nervous system diseases

Cp-MLR Directed Qsar Rationales for the Activity Profile of (Phenylpiperazinyl-Alkyl) Oxindoles as 5-Ht7 Receptor Ligands

Atropoisomerismo: o efeito da quiralidade axial em substâncias bioativas

Contact Info

Product

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Atropisomeric Derivatives of 2‘,6‘-Disubstituted (R)-11-Phenylaporphine: Selective Serotonin 5-HT₇ Receptor Antagonists

Recent progress in 5-HT₇receptors: potential treatment of central and peripheral nervous system diseases

Recent progress in 5-HT₇receptors: potential treatment of central and peripheral nervous system diseases