ACS Medicinal Chemistry Letters
Figure 2F), confirming the important role of I -IRs in the
cardiovascular properties of the novel compounds.
As expected, all compounds, and to a lower extent (R)-(−)-8,
displayed also bradicardic action (Figure 3), that was
comparable for 8 and 4 (Figure 3A).
Letter
(
ABBREVIATIONS
1
■
α -ARs, α -adrenoreceptors; HR, heart rate; IBS, imidazoline
binding site; I -IR, I -imidazoline receptor; MABP, mean
arterial blood pressure; PC-PLC, phosphatidylcholine-sensitive
phospholipase C; SHR, spontaneously hypertensive rats;
RVLM, rostral ventrolateral medulla; SAR, structure−activity
relationship; ip, intraperitoneal; ic, intracisternal
2
2
1
1
In conclusion, according to what was previously seen for
compound 4, the efficacious hypotensive effects of the novel
selective I -IR agonists 5, 8, and 9 confirmed that the
1
introduction of suitable substituents in the ortho position of
REFERENCES
■
the phenyl ring of the selective I -IR antagonist 3 was able to
1
(
1) Bousquet, P.; Feldman, J.; Schwartz, J. Central cardiovascular
effects of alpha adrenergic drugs: Differences between cathecolamines
and imidazolines. J. Pharmacol. Exp. Ther. 1984, 230, 232−236.
2) Ernsberg, P.; Giuliano, R.; Willette, R. N.; Reis, D. J. Role of
induce antagonism/agonism modulation. Obviously, such
modulation was affected by the physicochemical characteristics
of the decorations at the ortho position. In particular, in the
case of aromatic substituents, only a strong aromaticity (4 and
(
imidazole receptors in the vasodepressor response to clonidine
analogues in the rostral ventrolateral medulla. J. Pharmacol. Exp.
Ther. 1990, 253, 408−418.
5
) triggered efficacious I -IR interactions. Productive I -IR
1
1
interactions were also provided by aliphatic or halogen
substituents endowed with moderate steric hindrance and
positive lipophilic contributions (8 and 9). Nevertheless, the
fact that 8 (named carbomethyline) proved to have the highest
potency and longest lasting activity suggests that the van der
Waals interactions associated with the methyl group are
particularly advantageous. The aforementioned observations
(3) Tan, C. M.; Limbird, L. E. The α -adrenergic receptors. In The
2
Receptors: The Adrenergic Receptors in the 21st Century; Perez, D., Ed.;
Humana Press Inc.: Totowa, NJ, 2006; pp 241−265.
4) Fairbanks, C. A.; Stone, L. S.; Wilcox, G. L. Pharmacological
profile of alpha 2 adrenergic receptor agonists identified using
genetically altered mice and isobolographic analysis. Pharmacol. Ther.
(
2
009, 123, 224−238 and references therein..
will be useful in the design of novel I -IR agonists inspired by
1
(5) Hein, L. Adrenoceptors and signal transduction in neurons. Cell
Tissue Res. 2006, 326, 541−551.
our scaffold. Finally, similarly to what was verified for (S)-(+)-4,
the observation that only (S)-(+)-8 displayed significant
hemodynamic effects unequivocally confirmed the stereo-
(6) Dardonville, C.; Rozas, I. Imidazoline binding sites and their
ligands: an overview of the different chemical structures. Med. Res. Rev.
2004, 24, 639−661.
specific nature of the I proteins. It has also been reported
1
(
7) Nikolic, K.; Agbaba, D. Pharmacophore development and SAR
that I -IR agonists display positive effects on metabolic
1
studies of imidazoline receptor ligands. Mini-Rev. Med. Chem. 2012, 12,
542−1555.
8) Separovic, D.; Kester, M.; Haxhiu, M. A.; Ernsberg, P. Activation
of phosphatidylcholine-selective phospholipase C by I -imidazoline
receptors in PC12 cells and rostral ventrolateral medulla. Brain Res.
abnormalities, such as insulin resistance, impaired glucose
tolerance, and dyslipidemia. This cluster of dysfunctions,
together with hypertension, constitute the “syndrome X”,
which causes an elevated risk for cardiovascular disease and
1
(
1
25−28
premature death.
Therefore, the discovery of ligands
1
997, 749, 335−339.
devoid of the side effects induced by α -AR stimulation and that
2
(9) Greney, U.; Ronde, P.; Magnier, C.; Maranca, F.; Rascente, C.;
Quaglia, W.; Giannella, M.; Pigini, M.; Brasili, L.; Lugner, C.;
Bousquet, P. Coupling of I1 imidazoline receptors to the cAMP
pathway: studies with a highly selective ligand, Benazoline. Mol.
Pharmacol. 2000, 57, 1142−1151 and references therein..
selectively activate I -IRs can be regarded as a promising goal.
1
ASSOCIATED CONTENT
■
*
S
Supporting Information
(10) Zhang, J.; Abdel-Rahaman, A. A. Mitogen-activated protein
kinase phosphorylation in the rostral ventrolateral medulla plays a key
role in imidazoline (I )-receptor-mediated hypotension. J. Pharmacol.
Exp. Ther. 2005, 314, 945−952.
11) Tolentino-Silva, F. P.; Haxhiu, M. A.; Waldbaum, S.; Dreshay, I.
Synthetic procedure, X-ray crystallographic data for (S)-(+)-8,
experimental details of in vivo assays, and elemental analysis of
1
(
A.; Ernsberger, P. α -Adrenergic receptors are not required for central
2
Accession Codes
antihypertensive action of moxonidine in mice. Brain Res. 2000, 862,
2
(
6−35.
The X-ray coordinates of compound (S)-(+)-8 have been
deposited with Cambridge Crystallographic Data Centre with
accession number CCDC1025169.
12) Head, G. A. Central imidazoline-and alpha2-receptors involved
in the cardiovascular actions of centrally acting antihypertensive
agents. Ann. N.Y. Acad. Sci. 1999, 881, 279−286.
(13) Gentili, F.; Bousquet, P.; Brasili, L.; Dontenwill, M.; Feldman, J.;
AUTHOR INFORMATION
Ghelfi, F.; Giannella, M.; Piergentili, A.; Quaglia, W.; Pigini, M.
Imidazoline binding sites (IBS) profile modulation: Key role of the
bridge in determining I -IBS or I -IBS selectivity within a series of 2-
■
Corresponding Author
1
2
phenoxymethylimidazoline analogues. J. Med. Chem. 2003, 46, 2169−
2176.
(
14) Del Bello, F.; Diamanti, E.; Giannella, M.; Mammoli, V.;
Notes
Mattioli, L.; Titomanlio, F.; Piergentili, A.; Quaglia, W.; Lanza, M.;
Sabatini, C.; Caselli, G.; Poggesi, E.; Pigini, M. Exploring multitarget
interactions to reduce opiate withdrawal syndrome and psychiatric
comorbidity. ACS Med. Chem. Lett. 2013, 4, 875−879 and references
therein.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by grants from the University of
Camerino (Fondo di Ateneo per la Ricerca 2011-2012) and
Antica Farmacia Peroni, Pesaro. The authors express their
gratitude to Prof. Pascal Bousquet and Prof. Alan Hudson for
their suggestions for this manuscript.
(15) Gentili, F.; Ghelfi, F.; Giannella, M.; Piergentili, A.; Pigini, M.;
Quaglia, W.; Vesprini, C.; Crassous, P.-A.; Paris, H.; Carrieri, A. α2-
Adrenoreceptors profile modulation. 2. Biphenyline analogues as tools
for selective activation of the α -subtype. J. Med. Chem. 2004, 47,
2C
6160−6173.
5
00
ACS Med. Chem. Lett. 2015, 6, 496−501