Might the observed α(2A)-adrenoreceptor agonism or antagonism of allyphenyline analogues be ascribed to different molecular conformations?
Bioorg Med Chem
; 20(6): 2082-90, 2012 Mar 15.
Article
em En
| MEDLINE
| ID: mdl-22341244
ABSTRACT
We recently reported that the α(2)-adrenoreceptor (AR) ligand allyphenyline (9) significantly enhanced morphine analgesia (due to its α(2C)-AR agonism), was devoid of sedative side effects (due to its α(2A)-AR antagonism), prevented and reversed morphine tolerance and dependence. To highlight the molecular characteristics compatible with this behaviour and to obtain novel agents potentially useful in chronic pain and opioid addiction management, the allyl group of 9 was replaced by substituents of moderate steric bulk (MR) and positive or negative lipophilic (π) and electronic (σ) contributions in all the possible combinations. Effective novel α(2C)-agonists/α(2A)-antagonists (2, 3, 10, 12, and 17) were obtained. This study also demonstrated that contradictory combinations of the physicochemical parameters were similarly able to induce the α(2A)-activation. Since we had previously observed that the absolute configuration affected only the potency, but not the functional profile of the ligands, we hypothesized that the α(2A)-activation was governed by a ligand preferred conformation. From a structural overlay investigation it emerged that an extended conformation appeared to be associated with dual α(2C)-agonism/α(2A)-antagonism, whereas a folded conformation associated with α(2C)-/α(2A)-agonism.
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Base de dados:
MEDLINE
Assunto principal:
Receptores Adrenérgicos alfa 2
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Imidazolinas
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Compostos Alílicos
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Agonistas de Receptores Adrenérgicos alfa 2
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Antagonistas de Receptores Adrenérgicos alfa 2
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article