N-(phthalimidoalkyl) derivatives of serotonergic agents: a common interaction at 5-HT1A serotonin binding sites?

Glennon, Richard A.; Naiman, Noreen; Pierson, M. Edward; Smith, J D; Ismaiel, Abd M.; Titeler, Milt; Lyon, Robert A.

doi:10.1021/jm00128a039

Cited by 46 publications

(30 citation statements)

References 2 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…11 Except for some analogues, the affinity is weak as also reported separately for compound 1a. 12 Like for the other two groups of molecules, it appears that the THP analogues (1b, 1d, 1f, 1h, 1j, 1l) have a higher affinity than the corresponding piperazine analogues (1a, 1c, 1e, 1g, 1i, 1k). In THP series, the presence of a substituent in position 4 of the distal phenyl ring has no or minimal impact in terms of affinity, e.g., the unsubstituted derivatives (1b) and the 4-chloro analogue (1f) have a similar affinity of 706 and 631 nM, respectively.…”

mentioning

confidence: 95%

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

Liégeois

Lespagnard

Meneses‐Salas

et al. 2014

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

An electrostatic interaction related to a favorable position of the distal phenyl ring and a phenylalanine residue in the binding pocket would explain the higher 5-HT 1A affinity of a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue compared to the corresponding 4-phenylpiperazine analogue. To explore a possible reinforcement of this interaction to increase the affinity for 5-HT 1A receptors, different 4-substituted-phenyl analogues were synthesized and tested. The most important increase of affinity is obtained with two electron-donating methyl groups in positions 3 and 5. KEYWORDS: CH−π interaction, quinoxaline, carboxamide, arylpiperazine, electron-donating, docking R ecently, we reported that a 4-phenyl-1,2,3,6-tetrahydropyridine (THP) analogue was shown to be favorable compared to the corresponding 4-phenyl-piperazine one in terms of affinity for 5-HT 1A receptors in a series of 4-arylpiperazine-ethyl carboxamides. 1 An electrostatic interaction between the distal benzene ring of the molecule and a phenylalanine residue (Phe 6.52) particularly in the 5-HT 1A receptor binding pocket was suggested by molecular modeling approaches. 2 The almost coplanar orientation of both rings displayed in the 4-phenyl-THP compound appeared as an important spatial requirement for an optimal interaction with the 5-HT 1A receptor in the present series. This orientation should stabilize the ligand binding by an edge-to-face CH−π interaction between the phenyl ring of the 4-phenyl-THP compounds and the phenyl ring of the Phe 6.52 residue. 2 This would explain why the chemical modification of the piperazine ring into THP is favorable for receptor affinity.The electron donating/withdrawing properties of an aromatic substituent is an important factor for the electron density of the aromatic ring and consequently for the capacity of these rings to be involved in aromatic stacking interactions. 3 Some studies have already shown the impact of the electronic properties of the substituents on the stability of these interactions in ligand−receptor binding. 4,5 Therefore, by increasing the electronic density with an electron-donating group, we expected to reinforce the interaction between the distal benzene ring and the Phe 6.52 residue. The substituents were positioned either in position 4 or positions 3 and 5 of the distal ring in order to avoid a sterical constraint if present in position 2 or 6. To explore a possible opposite effect linked to the electronic properties of the substituents, electron-withdrawing atoms were also introduced. The THP derivatives were tested, in parallel with the corresponding arylpiperazine derivatives, for their affinity for 5-HT 1A receptors. The intrinsic activity of six selected compounds was also investigated using an electrophysiological approach.The target compounds were prepared by reaction of the appropriate primary amine with the appropriate acyl chloride (2-naphthoyl chloride or 2-quinoxaline chloride) as reported in Scheme 1. The crude amines were synthesized following a Gabriel pro...

show abstract

mentioning

confidence: 95%

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

Liégeois

Lespagnard

Meneses‐Salas

et al. 2014

ACS Med. Chem. Lett.

View full text Add to dashboard Cite

show abstract

“…Elemental analyses were performed in the Institute of Organic Chemistry PAS (Warsaw, Poland), and were within 0.5% of the theoretical values. The syntheses of 2-(4-aminobutyl)-1,2,3,4-tetrahydroisoquinoline [9] and 4-(4-aminobutyl)-1-(2-methoxyphenyl)piperazine [15] have been previously reported.…”

Section: Generalmentioning

confidence: 99%

New Imide 5-HT1A Receptor Ligands – Modification of Terminal Fragment Geometry

et al. 2004

View full text Add to dashboard Cite

Two sets of new o-methoxyphenylpiperazine (MPP; series a) and 1,2,3,4-tetrahydroisoquinoline (THIQ; series b) derivatives, containing various imide moieties derived from NAN190, were synthesized and evaluated in vitro for their ability to bind to the serotonin 5-HT 1A and 5-HT 2A receptors. All new derivatives from series a demonstrated high 5-HT 1A affinities, whereas THIQ analogues were much less active. With respect to 5-HT 2A receptors, three MPP derivatives presented moderate activity but the rest of the investigated compounds were practically inactive. The influence of changes in terminus geometry on 5-HT 1A receptor affinity was analyzed in regard to model compounds NAN190 and MM199.

show abstract

“…A inserção de FPZ no modelo de receptor 5-HT 1A revelou a possibilidade de sua subunidade aromática posicionar-se tanto sobre a subunidade aromática (A) 138 quanto a pirrólica (B) da 5-HT 139 , por meio de interações com seus elétrons π (Figura 12).…”

Section: Posicionamento De Fpz No Modelo De Receptorunclassified

“…Estudos realizados por Kuipers e colaboradores 96 permitiram evidenciar que as melhores correlações entre estrutura/atividade de FPZ ocorrem quando a orientação do anel benzênico desses compostos coincide com o anel pirrólico da 5-HT, de acordo com a proposição de Glennon e colaboradores 96,139 . Neste contexto, a afinidade pelo receptor 5-HT 1A decresce com a substituição nas posições 3 e 4 do composto 48 (Figura 13), de acordo com os efeitos negativos observados pela substituição nas posições 7 e 1 de 5-HT 138,140 .…”

Section: Posicionamento De Fpz No Modelo De Receptorunclassified

“…Neste contexto, a afinidade pelo receptor 5-HT 1A decresce com a substituição nas posições 3 e 4 do composto 48 (Figura 13), de acordo com os efeitos negativos observados pela substituição nas posições 7 e 1 de 5-HT 138,140 . Da mesma forma, o efeito da introdução de substituintes volumosos na posição 6 dos compostos 45 e 48 assemelha-se às modificações correspondentes à posição 2 de 5-HT e RU24969 (29), mostrando-se desfavoráveis para a afinidade do re- 139,141 . Por outro lado, a presença dos respectivos substituintes hidroxila e metoxila em 5-HT e 29 são essenciais para a alta afinidade destes compostos 96 (Figura 13).…”

Section: Posicionamento De Fpz No Modelo De Receptorunclassified

See 1 more Smart Citation

Novas estratégias terapêuticas para o tratamento da depressão: uma visão da química medicinal

2003

View full text Add to dashboard Cite

Depression is a widespread humor disturbance promoted mainly by depletion of biogenic neurotransmitter amines involved in the CNS synapses. Effective drug treatments for depression have been available for more than forty years. Despite its remarkable structural diversity, this paper discuss under the medicinal chemistry point of view, all different classes of "monoamine based" antidepressant drugs, emphasizing the rational design, structure-activity relationships (SAR), biotransformation and physicochemical properties related with antidepressant activity and molecular mechanism of action.Keywords: monoamine oxidase inhibitors; monoamine reuptake inhibitors; serotonin receptor antagonists. INTRODUÇÃOOs distúrbios do humor são graves perturbações do estado emocional, que devem ser distinguidos das alterações do afeto, i.e. manifestações externas de um estado emocional interno 1 . Depressão e mania são freqüentemente considerados como pontos extremos da alteração do humor ou afetiva. Classicamente, estes distintos pólos da variação do humor originaram os termos unipolar, para o estado depressivo, no qual pacientes evidenciam acentuada diminuição do estado normal de humor, e distúrbio bipolar, em que os pacientes alternam, em diferentes momentos, quadros de diminuição (depressão) e exacerbação (mania) de humor. Na prática, a depressão e a mania podem ocorrer simultaneamente, caracterizando um estado afetivo misto 2 . A depressão consiste em um sentimento que é universalmente experimentado por todos os seres humanos no decorrer de suas vidas. A distinção entre o sentimento depressivo normal e o quadro patológico, que necessita de tratamento médico, é extremamente problemática para pessoas não especializadas em saúde mental. Neste contexto, estigmas e desinformação levaram à crença de que a depressão não seria doença, mas consistiria numa deficiência de cará-ter, a qual poderia ser superada com esforço pelo indivíduo. Os critérios de diagnóstico dos distúrbios de humor estão em constante evolução, com atualizações nosológicas agrupadas no Manual de Diagnóstico e Estatística dos Distúrbios Mentais (DMS-IV) 3 . A qualidade do humor, seu grau de desvio da normalidade e sua duração são características chave de um distúrbio afetivo. Contudo, em adição, os clínicos devem avaliar outros sintomas, na formulação de um diagnóstico mais preciso, como as características vegetativas, e.g. sono, apetite, peso e libido; cognitivas, e.g. atenção, tolerância à frustração, memória; comportamentais, e.g. motivação, prazer, interesse, fadiga; físicas ou somáticas, e.g. cefaléia, dores estomacais e tensão muscular e controle do impulso, e.g. suicídio e homicídio. Dados da Organização Mundial de Saúde (OMS) indicam que13-20% da população mundial apresentam sintomas depressivos, sendo 2-3% desse total atribuídos a indivíduos com transtornos afetivos graves, dos quais 15-30% cometem suicídio ou são potenciais suicidas. Mesmo sob tratamento médico, 30% dos pacientes com diagnóstico depressivo não respondem à terapia farmacológica, devido ao t...

show abstract

N-(phthalimidoalkyl) derivatives of serotonergic agents: a common interaction at 5-HT1A serotonin binding sites?

Cited by 46 publications

References 2 publications

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

New Imide 5-HT1A Receptor Ligands – Modification of Terminal Fragment Geometry

Novas estratégias terapêuticas para o tratamento da depressão: uma visão da química medicinal

Contact Info

Product

Resources

About

N-(phthalimidoalkyl) derivatives of serotonergic agents: a common interaction at 5-HT1A serotonin binding sites?

Cited by 46 publications

References 2 publications

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT1A Receptors

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT1A Receptors

New Imide 5-HT1A Receptor Ligands – Modification of Terminal Fragment Geometry

Novas estratégias terapêuticas para o tratamento da depressão: uma visão da química medicinal

Contact Info

Product

Resources

About

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors

Enhancing a CH−π Interaction to Increase the Affinity for 5-HT_1A Receptors