PMID- 22341244
OWN - NLM
STAT- MEDLINE
DCOM- 20120711
LR  - 20120309
IS  - 1464-3391 (Electronic)
IS  - 0968-0896 (Linking)
VI  - 20
IP  - 6
DP  - 2012 Mar 15
TI  - Might the observed alpha(2A)-adrenoreceptor agonism or antagonism of allyphenyline 
      analogues be ascribed to different molecular conformations?
PG  - 2082-90
LID - 10.1016/j.bmc.2012.01.035 [doi]
AB  - We recently reported that the alpha(2)-adrenoreceptor (AR) ligand allyphenyline (9) 
      significantly enhanced morphine analgesia (due to its alpha(2C)-AR agonism), was 
      devoid of sedative side effects (due to its alpha(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 (pi) and electronic (sigma) contributions in all the possible 
      combinations. Effective novel alpha(2C)-agonists/alpha(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 
      alpha(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 alpha(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 
      alpha(2C)-agonism/alpha(2A)-antagonism, whereas a folded conformation associated with 
      alpha(2C)-/alpha(2A)-agonism.
CI  - Copyright A(c) 2012 Elsevier Ltd. All rights reserved.
FAU - Diamanti, Eleonora
AU  - Diamanti E
AD  - Scuola di Scienze del Farmaco e dei Prodotti della Salute, Universita degli Studi 
      di Camerino, via S. Agostino 1, 62032 Camerino, Italy.
FAU - Del Bello, Fabio
AU  - Del Bello F
FAU - Carbonara, Giuseppe
AU  - Carbonara G
FAU - Carrieri, Antonio
AU  - Carrieri A
FAU - Fracchiolla, Giuseppe
AU  - Fracchiolla G
FAU - Giannella, Mario
AU  - Giannella M
FAU - Mammoli, Valerio
AU  - Mammoli V
FAU - Piergentili, Alessandro
AU  - Piergentili A
FAU - Pohjanoksa, Katariina
AU  - Pohjanoksa K
FAU - Quaglia, Wilma
AU  - Quaglia W
FAU - Scheinin, Mika
AU  - Scheinin M
FAU - Pigini, Maria
AU  - Pigini M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120131
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (2-(1-(2-allylphenoxy)ethyl)-4,5-dihydro-1H-imidazole)
RN  - 0 (Adrenergic alpha-2 Receptor Agonists)
RN  - 0 (Adrenergic alpha-2 Receptor Antagonists)
RN  - 0 (Allyl Compounds)
RN  - 0 (Imidazolines)
RN  - 0 (Receptors, Adrenergic, alpha-2)
SB  - IM
MH  - Adrenergic alpha-2 Receptor Agonists/*chemistry/*pharmacology
MH  - Adrenergic alpha-2 Receptor Antagonists/*chemistry/*pharmacology
MH  - Allyl Compounds/*chemistry/*pharmacology
MH  - Animals
MH  - CHO Cells
MH  - Cricetinae
MH  - Humans
MH  - Imidazolines/*chemistry/*pharmacology
MH  - Molecular Conformation
MH  - Molecular Dynamics Simulation
MH  - Receptors, Adrenergic, alpha-2/*metabolism
EDAT- 2012/02/22 06:00
MHDA- 2012/07/12 06:00
CRDT- 2012/02/21 06:00
PHST- 2011/11/21 00:00 [received]
PHST- 2012/01/18 00:00 [revised]
PHST- 2012/01/21 00:00 [accepted]
PHST- 2012/02/21 06:00 [entrez]
PHST- 2012/02/22 06:00 [pubmed]
PHST- 2012/07/12 06:00 [medline]
AID - S0968-0896(12)00065-X [pii]
AID - 10.1016/j.bmc.2012.01.035 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2012 Mar 15;20(6):2082-90. doi: 10.1016/j.bmc.2012.01.035. Epub 
      2012 Jan 31.