A. Sparatore, F. Sparatore / Il Farmaco 56 (2001) 169–174
173
[2] J. Thuillier, P. Rumpf, G. Thuillier, Derivatives of acids regula-
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aminoethyl ester of p-chlorophenoxyacetic acid, Compt. Rend.
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using NAI (Nurnberger Alters-Inventar) on patients with or-
ganic psychosyndrome (DSM III, Category I) treated with cen-
5. Results and discussion
Results of binding assays on central muscarinic re-
ceptors (on a non selective basis) are presented in Table
1.
With the exception of compounds 4 and 8 (only
moderately active), the prepared esters exhibited good
affinity for central muscarinic receptors ([3H]QNB dis-
placement assay) with pKi in the range 6.67–7.68.
The comparison of data relative to aryloxyalkanoic
esters and the corresponding arylthioalkanoic esters
clearly indicate the affinity enhancing effect of the
sulphur bridge, which is particularly strong in the case
of unsubstituted unbranched esters 8 and 11.
Aryloxy- and arylthiopropionic esters were always
more active than the corresponding acetic derivatives,
while the further chain elongation produced a further
increase of affinity only in the set of phenylthioalkanoic
esters 11–13. Thus lupinine 2-(phenylthio)butyric ester
(13) exhibited the highest affinity (pKi=7.68) which is
comparable with that of tropanol 2-(phenylthio)-
butyrate [23].
In the set of arylthioalkanoic esters the p-chloro
substitution produces a general decrease of affinity,
however a slight increase of affinity was observed when
comparing phenoxyacetic esters 8 and 4; thus more
data are necessary to soundly assert the effect of para
chloro substitution in these kinds of compounds.
The ester 13, which exhibited the highest affinity to
muscarinic receptors, was assayed for affinity to central
nicotinic receptor and for inhibitory activity on acetyl-
cholinesterase. At a concentration 10 mM this com-
pound failed completely in displacing [3H]cytisine from
nicotinic receptor and also in the inhibition of acetyl-
thiocholine hydrolysis by means of the human erythro-
cytes enzyme.
trophenoxine in
a double-blind, comparative, randomized
clinical trial, Arch. Gerontol. Geriatr. 9 (1989) 17–30.
[4] G. Thuillier, P. Rumpf, Pre´paration de nouveaux esters et
amides basiques des acides qui agissent comme re´gulateurs de
croissance des ve´ge´taux. Relations entre la structure et l’activite´
biologique, Bull. Soc. Chim. Fr. (1960) 1786–95.
[5] G. Thuillier, S. Marlier, B. Saville, P. Rumpf, Pre´paration de
nouveaux esters et amides basiques des acides qui agissent
comme re´gulateurs de croissance des ve´ge´taux. II. Isoste`rs
soufre´s et azote´s, Bull. Soc. Chim. Fr. (1963) 1084–6.
[6] G. Thuillier, J.M. Dumont, A. Vilar, P. Rumpf, Pre´paration de
nouveaux esters et amides basiques des acides qui agissent
comme re´gulateurs de croissance des ve´ge´taux. III. Amides, Bull.
Soc. Chim. Fr. (1963) 1087–90.
[7] J. Thuillier, H. Nakajima, J.L. Grandjean, J. L’Huillier, Correla-
tion entre l’effet de de´rive´s de l’acide phe´noxyacetique sur cer-
tains tests pharmacologiques et leur effet antidepresseur en
clinique humaine, Biochem. Pharmacol. 12, suppl. (1963) 56.
[8] G. Thuillier, J. Thuillier, Chimie et pharmacologie de nouveaux
antide´presseurs de´rive´s des auxines, Arzneim. Forsch. 14 (1964)
556–558.
[9] E. Kreppel, Tierexperimentelle Untersuchungen zum zentralen
Wirkungscharakter von Chloropromazin, Imipramin und einigen
Auxin-Derivaten, Arzneim. Forsch. 14 (1964) 559–561.
[10] K. Karzel, Zur Wirkung einiger neuer antidepressive wirksamer
Auxine-Derivate, Arzneim. Forsch. 14 (1964) 561–562.
[11] G. Thuillier, De´rive´s des acides aryloxyace´tiques a` activite´ neu-
rotrope, Chim. Ther. 1 (1966) 82–86.
[12] W.G. v. Staehr, K. Karzel, Einfluss von Auxinen und Auxin-
derivaten auf Lebens- und Vermehrungsfa¨higkeit tierischer Tu-
morzellen in vitro, Chim. Ther. 1 (1966) 444–451.
[13] N.A. Zakharova, N.V. Khromov-Borisov, M.L. Indenbom, Sev-
eral derivatives of p-chlorophenoxyacetic acid, Biol. Aktivn.
Soedin. Akad. Nauk. SSSR (1965) 112–116; Chem. Abstr. 63
(1965) 17948a.
[14] V. Boido, F. Sparatore, Derivati di amminoalcoli e di diammine
naturali d’interesse farmacologico. Nota V. Nuovi derivati della
lupinina e dell’amminolupinano. Prime notizie sulla loro attivita`
farmacologica, Ann. Chim. 59 (1969) 526–538.
[15] Unpublished results from Bristol Laboratories, Syracuse, NY.
[16] D.T. Witiak, H.A.I. Newman, D.R. Feller, Clofibrate and Re-
lated Analogs, Marcel Dekker, New York, 1977, pp. 122–138.
[17] R.H. Superko, Drug therapy and the prevention of atherosclero-
sis in humans, Am. J. Cardiol. 64 (1989) 31G–38G.
Concluding, the prepared esters display a generally
good affinity for muscarinic receptors, however, in or-
der to plan appropriately targeted in vivo studies, fur-
ther assays are needed to define their affinities for M1,
M2 and M3 receptor subtypes.
[18] D.R. Feller, V.S. Kamanna, H.A.I. Newman, K.J. Romsted,
D.T. Witiak, G. Bettoni, S.H. Briant, D. Conte-Camerino, F.
Loiodice, V. Tortorella, Dissociation of hypolipidemic and an-
tiplatelet actions from adverse myotonic effects of clofibric acid
and related enantiomers, J. Med. Chem. 30 (1987) 1265–1267.
[19] F. Novelli, F. Sparatore, Thiolupinine and some derivatives of
pharmacological interest, Farmaco 48 (1993) 1021–1049.
[20] F. Novelli, B. Tasso, F. Sparatore, Synthesis and pharmacologi-
cal evaluation of some thiolupinine derivatives, Farmaco 54
(1999) 354–358.
[21] F. Savelli, F. Sparatore, Esteri della retamina d’interesse farma-
cologico, Studi Sassaresi 53 (1975) 409–23; Chem. Abstr. 88
(1978) 69047.
[22] F. Gualtieri, G. Conti, S. Dei, M.P. Giovannoni, F. Nannucci,
M.N. Romanelli, S. Scapecchi, E. Teodori, L. Fanfani, C. Ghe-
lardini, A. Giotti, A. Bartolini, Presynaptic cholinergic modula-
Acknowledgements
The financial support of the ‘Ministero dell’Univer-
sita` e della Ricerca Scientifica e Tecnologica’ is grate-
fully acknowledged.
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