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1165
5. Yanagi, H.; Sankawa, H.; Saito, H.; Iikura, Y. Acta
Anaesthesiol. Scand. 1996, 40, 1138.
6. Tanaka, A.; Minoguchi, K.; Oda, N.; Yokoe, T.; Matsuo,
H.; Okada, S.; Tasaki, T.; Adachi, M. J. Allergy Clin.
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tamine-induced contraction, whereas analogues 28, 30,
and 39 were shown to be equieffective against both stim-
uli (Table 3).
The separation of anesthetic and antispasmodic activi-
ties of these compounds attests to the diversity of possi-
ble interactions by substances of this type. It has been
reported that the IC50 value for blockade of sodium cur-
rents after treatment with the analogue 40 (also named
JMF2-1) (25.4 mM) was remarkably higher than that
of lidocaine (0.18 mM), which is consistent with the
weak anesthetic capacity of this analogue.13 These find-
ings are also consistent with the interpretation that neb-
ulized JMF2-1 might be a way of achieving the anti-
asthma effects of lidocaine without the anesthetic effects.
7. Kai, T.; Nishimura, J.; Kobayashi, S.; Takahashi, S.;
Yoshitake, J.; Kanaide, H. Anesthesiology 1993, 78, 954.
8. Hunt, L. W.; Swedlund, H. A.; Gleich, G. J. Mayo Clin.
Proc. 1996, 71, 361.
9. Hunt, L. W.; Frigas, E.; Butterfield, J. H.; Kita, H.;
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10. Nau, C.; Wang, G. K. J. Membr. Biol. 2004, 201, 1.
11. Lo¨fgren, N. M.; Lundqvist, B. J. U.S. Patent 2, 441, 498,
1948.
12. Synthesis of compound 1 (lidocaine hydrochloride) and its
analogues (28–40). Aniline 2–11 (0.25 M) in toluene
(300 mL) and sodium carbonate (53 g, 0.50 M) at 20–
30 ꢁC were added little by little over 30 min to 2-
chloroacetyl chloride or 3-chloropropionyl chloride
(0.30 M). The mixture was stirred for one hour at room
temperature, diluted with water (100 mL), and diethyl-
amine (0.74 M) was added. The reaction mixture was
refluxed for 6–10 h, the organic layer collected and washed
three times with water (3 · 100 mL). The organic solvent
was removed under vacuum to leave a crude product which
was dissolved in acetone (100 mL), and charcoal (2.0 g)
was added at room temperature. After 30 min under
stirring the suspension was filtered. The solution was kept
at 10–15 ꢁC and a flux of HCl (g) was passed into the
solution until pH = 2–3. The product was filtered and
recrystallized from acetone to give the lidocaine hydro-
chloride or its analogues (28–40).
13. Costa, J. C. S.; Olsen, P. C.; Siqueira, R. A.; Carvalho, V.
F.; Serra, M. F.; Alves, L. A.; Faria, R. X.; Xisto, D. G.;
Rocco, P. R. M.; Cordeiro, R. S.; Silva, P. M. R.; Martins,
M. A. J. Allergy Clin. Immunol. 2007, 119, 219.
14. Anesthetic Activity Assay: Anesthetic activity was deter-
mined by nocifensive cutaneous reaction in naive rats on
the basis of the withdrawal reflex toward pinching on
cutaneous sites on their backs which were previously
injected with increasing doses of lidocaine or analogues
(0.5–4.0 lmol/site) in a final volume of 50 lL in 5 min
intervals. An area of anesthesia was considered present
when the rat did not squeak or withdraw the skin within 4
seconds of starting skin clamping as described.15 All
solutions of lidocaine and analogues were prepared using
physiological saline (0.9% NaCl solution).
In summary, various lidocaine analogues have been
found to exhibit reduced local anesthetic activities but
superior potencies to inhibit allergen- and histamine-
evoked intestinal contraction than lidocaine itself.
Changes in the aromatic ring substitution of lidocaine
led to enhanced potency and selective antispasmodic
activity. Changes in the torsional angles between the aro-
matic ring and the plane of the aliphatic side chain and in-
creased lipophilicity of these compounds are likely to
account for the observed results. These findings reinforce
the concept that the anesthetic and antispasmodic activi-
ties of lidocaine are dissociated. Selected analogues ob-
tained in this study can be considered as new templates
in drug discovery for smooth muscle disorders, with fewer
expected side effects on cardiac and neuronal excitability.
Acknowledgments
The authors thank Solange M.S.V. Wardell and James L.
Wardell for helping with the grammatical revision and
useful discussions. This work was supported by grants
´
from Conselho Nacional de Desenvolvimento Cientıfico
´
Tecnologico (CNPq), Programa PDTIS-Fiocruz
(RMB22), andFundac¸a˜oCarlos ChagasFilho deAmpar-
e
`
o a Pesquisa do Estado do Rio de Janeiro (FAPERJ).
15. Takagi, H.; Inukai, T.; Nakama, M. Jpn. J. Pharmacol.
1966, 16, 287.
Supplementary data
16. Schleifer, K. J.; Tot, E.; Holtje, H. D. Pharmazie 1998, 53,
596.
17. Mcmaster, P. D.; Noris, V. J.; Stankard, C. E.; Byrnes, E.
W.; Guzzo, P. R. Pharm. Res. 1991, 8, 1013.
18. Ulbricht, W. Physiol. Rev. 2005, 85, 1271.
Details of compound characterization have been in-
cluded as supporting material. Supplementary data
associated with this article can be found, in the online
19. Yarov-Yarovoy, V.; McPhee, J. C.; Idsvoog, D.; Pate, C.;
Scheuer, T.; Catterall, W. A. J. Biol. Chem. 2002, 277,
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References and notes
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