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Amselamine, a new selective histamine H2-receptor agonist
JIborganic & Medici~l Che&~
Letters, Vol. 4, No. 16, pp. 1913-1916. 1994 copyright 0 1994 Elscvicr science Ltd Printed in Great Britain. All rights rimed ~8~~ S7.W+O.O0
~~-894X(94)~263-0
AMSELAMINE, A NEW SELECTIVE HISTAMINE Ha-RECE~OR AGONISI?
Henk van der Goot*, John Ch. Rriks, Rob Leurs and Hendrilr Timmerman L.&&niA~~~ter&mCenterfor Drug Research Dab
of P~~~~*
Free ~~~er~~, De Boelekm 1083,
NL408f W Amsterdam.The Netherlands
Abstract. The synthesis of amselamine (2-~no-5~(2-amin~~yl)-4-~~yl-1,3-selenazole~, a potent histamine H2-agomst, has bear described. At the guinea prg right atnum amselamine mvealed to be slightly more active than rts sulfur analogue amthamine and htstamine. Moreover negligible effects on Ht and H3-receptors were obeserved.
During long time the possibility of a tautomeSc shift of the ligand, as can be very easily achieved in the huidazole structure of histamine (1). has been thought to be a su~ural Q-receptort.
requirement for the stimulation of the histamine
Although several authors questioned the necessity of a tautomeric shiit2, recently Rriks et ah3
provided evidence that also non-tautomeric structures can be %-agonists. Examples are found in a series of tbiftxoles, with ~~~~
(2a) being the most active compound of the series.
Smce it has been shown that in these type of compounds the pKa of the heterocyclic system is determining the affinity to the h-receptor,
it is interesting to vary X in structure 2 in order to modify the pKa of the ring system.
JWiminary calculations revealed that the selenaxole 2b might be expected to possess fairly high histamine Hzagonistic activity. Themfore thii compound was prepared and ~~~10~~~
evaluated.
The selenaxole 2b was prepared as indicated in scheme LThe phthalimidobmmopentanone4 with selenourea
(4) in refluxing
ph~~&~~yl]-l,3-~len~le
ethanol
during
6 hrs. After cooling
(5) was ftltered off as the hydride
95%. melting point 206.2 - 208.9V. # To the memory of John ~riks who died October 26*. 1992. 1913
3 was condensed
2-amino-4-methyl-5-[2-(N-
and crystalked
from ethanol. Yield
i% VAN DER GOOT et al.
1914
Scheme 1
48% Hsr
lH-NMR (200 mHz) in de-DMSO: 1.90 ppm (singlet, CH$, 2.94 ppm (triplet, J = 6.1 Hz, ArCH& 3.96 ppm (triplet, J = 6.1 Hz, NCH& 7.88 ppm (singlet, 4 x ArH), 9.36 ppm (broad singlet, NH$, 12.52 ppm (broad singlet, +NH). Subsequently the phthalimidoselcnaxob 5 was hydrolyzed in refluxing 48% HRr during 5 hrs. After evaporation to dryness the residue (2b) was crystallixed thme times from ethanol. Yield 56% melting point 249.6 - 250.0°C. lH-NMR (ZOOmHz) in d6-DMSO: 2.11 ppm (singlet, CH3), 2.99 ppm ( singlet, 2 x CHz), 8.00 ppm (broad singlet, +NH$, 9.39 ppm (broad singlet, NH& 12.65 (broad singlet, ‘NH). Mass spectrum (RX,70 eV): found n$e = 205.0129, calculated for C~HttN~~Se: 205.0118. Titration with 0.1 N NaOH in water containing 0.162 M KN03 revealed that the equivalent weight of the sample prepared was 99.8% of the theoretical value. The pKa values calculated from the titration curve are indicated in table 1. Results of elemental analysis were within 0.4 % of the theoretical value for C, H and N.
Histamine Hz_activity was determined on the isolated spontaneously beating guinea pig right atrium acconiing to Sterk et aL5 The pDz values were derived from the 50% level of the maximum response of the agonistic doseresponse curves. Affvrity to the %-receptor was determined on rat histamine Hz-receptors expressed in CHO cell as described by Traiffort et al6 using [ 12sIJ-i~oa~no~tentidine
as the ~ioligan~
the dispIacement
curves were analysed with the program LIGAND’. Amsela~e
(2b) behaves as a full agonist with a pD2 value of 6.41 which makes it slightly more potent than
histamine and amthamine (ta). Its H2-agonistic character was verified with cimetkline as antagonist. Cimetidiie appeared to be a competitive antagonist with a pAZ value of 6.41 f 0.04 (3) with amselamine as agonist, which is in accordance with repotted values using other agonists2. Dose-response curves are shown in fig. 1.
1915
Amselamine, an Hz-receptor agonist
Table 1 Phamn~logical
data and basic@ of ~-agonists.
X
pD, f s.e.m’
2b
Se
8.41 f 0.06 (6)
2a
s
0.21 f 0.09 (7) 6.14 f 0.04 (22)
3.93 f 0.06 (3)
histamb
pKd f s.e.m.b
pK,, f 8.c.m C
pKa2 f s.e.m d
5.01 f 0.02 (3)
9.21 f 0.01 (4)
5.78 f 0.01 (4)
4.94 f 0.06 (3)
9.15 f 0.02 (6)
5.40 f 0.01 (6)
9.32 f 0.14 (3)
5.93 f 0.14 (3)
a Guinea pig right atrium; b. CHO rat Hg cells; c. aliihatic amine; d heterocyclic ring. Amselamine shows very wesk intemctio~~swith histamine HI- and H3-receptors. Thus concerning HI-activity
(guinea pig ileum) a p4-value
of 3.85 f 0.07 (4) against histamine was found, whereas in the test for Hs-
activity (electrically stimulated guinea pig jejunum)l a pDz-value of 4.44 f 0.05 (3) was established. These results make am&amine a selective and relatively potent histamine $-agonist. Fig. 1 Functional effects of amselamine on histamine %-receptors. (Guinea pig right atrium, chronotropic effect)
-9 o
-6
-7
-6
-5
-4
-3
Lo(([l
Histaminc. l Am&mine w Amselamine + 104 M Cimetidine and A Amselamine + lO_3 M Cimetidine.
Recently we provided evidences that monocations of histamine, dimaprit and a number of thiazoles exert their interaction with the histamine %-receptor
through H-bond formation with the primary ammonium group,
protonation of the aromatic N-atom and H-bond formation (if X = NH) or electrostatic interaction (if X = S) as
H.
1916
shown in fig. 2. Fig. 2
VAN DEB
GOOT et al.
Binding to the histaxnim H2-receptor
Since the selenazole ring of amsehmine is somewhat more basic than the thlazole ring of amthamlne (table 1). it may be expected that amselamlne has a slightly higher affinity for the H2-receptor than an&amine. However, since amthamlne and amselamine exert almost equal affinltiea for the histamine %-receptor on CHO cells, such a statistically significant higher affinity was not established.
It appeared that the seleno analogue of the potent histamine HTagonist amthamine, which is designated as amselamine. behaves as a potent histamine h-agonist with a higher potency than histamine itself. Moreover amselamine exerts hardly any activity for histamine Ht- and Hj-receptors, which makes it selective for the histamine q-receptor. Acknowledgement.The
research of Dr. R. Leurs has been made possible by a fellowship of the Royal
Netherlands Academy of Arts and Sciences.
1. Weinstein. H.; Chou, D.; Johnson, C.L.; Kang, S.; Green, J.P. Mol. Pharmacol. 1976.12.738. 2. Van der Goat, H.; Bast, A.; Timmerman, H. Handbook of Experimental Pharmacology; Uvnls, B., Ed.; 3. 4. 5. 6
Springer-Verlag: Berlin, 1991; Vol. 97, pp. 573 - 748. Exiks, J.C.; Van der Goot, H.; Timmerman, H. Mol. Pharmacol. 1993,44,886. Eriks. J.C.; Van der Goat, H.; Sterk, G.J.; Timmerman, H. J. Med. Chem. 1992.35, 3239. Sterk, G.J.; Van der Goat, H.; Tiierman, H. Eur. J. Med. Chem. 1984,19,545. Tralffort. E.; Ruat, M.; Arrang, J.M.; Leurs, R.; Pomelli, D.; Schwartz, J.C. Proc. Natl. Acad. Sci. 1992,
89, 2649. 7 Munson, P.J.; Rodbard, D. Anal. Biochem. 1980,107,220. 8. Vollinga, R.C.; Zuiderveld, O.P.; Scheerens. H.; Bast, A.; Timmexman. H. Meth. Find. Exp. Clin. Phannacol. 1992.14.747.
(Received in Belgium 3 March 1994; accepted 19 May 1994)
Letters, Vol. 4, No. 16, pp. 1913-1916. 1994 copyright 0 1994 Elscvicr science Ltd Printed in Great Britain. All rights rimed ~8~~ S7.W+O.O0
~~-894X(94)~263-0
AMSELAMINE, A NEW SELECTIVE HISTAMINE Ha-RECE~OR AGONISI?
Henk van der Goot*, John Ch. Rriks, Rob Leurs and Hendrilr Timmerman L.&&niA~~~ter&mCenterfor Drug Research Dab
of P~~~~*
Free ~~~er~~, De Boelekm 1083,
NL408f W Amsterdam.The Netherlands
Abstract. The synthesis of amselamine (2-~no-5~(2-amin~~yl)-4-~~yl-1,3-selenazole~, a potent histamine H2-agomst, has bear described. At the guinea prg right atnum amselamine mvealed to be slightly more active than rts sulfur analogue amthamine and htstamine. Moreover negligible effects on Ht and H3-receptors were obeserved.
During long time the possibility of a tautomeSc shift of the ligand, as can be very easily achieved in the huidazole structure of histamine (1). has been thought to be a su~ural Q-receptort.
requirement for the stimulation of the histamine
Although several authors questioned the necessity of a tautomeric shiit2, recently Rriks et ah3
provided evidence that also non-tautomeric structures can be %-agonists. Examples are found in a series of tbiftxoles, with ~~~~
(2a) being the most active compound of the series.
Smce it has been shown that in these type of compounds the pKa of the heterocyclic system is determining the affinity to the h-receptor,
it is interesting to vary X in structure 2 in order to modify the pKa of the ring system.
JWiminary calculations revealed that the selenaxole 2b might be expected to possess fairly high histamine Hzagonistic activity. Themfore thii compound was prepared and ~~~10~~~
evaluated.
The selenaxole 2b was prepared as indicated in scheme LThe phthalimidobmmopentanone4 with selenourea
(4) in refluxing
ph~~&~~yl]-l,3-~len~le
ethanol
during
6 hrs. After cooling
(5) was ftltered off as the hydride
95%. melting point 206.2 - 208.9V. # To the memory of John ~riks who died October 26*. 1992. 1913
3 was condensed
2-amino-4-methyl-5-[2-(N-
and crystalked
from ethanol. Yield
i% VAN DER GOOT et al.
1914
Scheme 1
48% Hsr
lH-NMR (200 mHz) in de-DMSO: 1.90 ppm (singlet, CH$, 2.94 ppm (triplet, J = 6.1 Hz, ArCH& 3.96 ppm (triplet, J = 6.1 Hz, NCH& 7.88 ppm (singlet, 4 x ArH), 9.36 ppm (broad singlet, NH$, 12.52 ppm (broad singlet, +NH). Subsequently the phthalimidoselcnaxob 5 was hydrolyzed in refluxing 48% HRr during 5 hrs. After evaporation to dryness the residue (2b) was crystallixed thme times from ethanol. Yield 56% melting point 249.6 - 250.0°C. lH-NMR (ZOOmHz) in d6-DMSO: 2.11 ppm (singlet, CH3), 2.99 ppm ( singlet, 2 x CHz), 8.00 ppm (broad singlet, +NH$, 9.39 ppm (broad singlet, NH& 12.65 (broad singlet, ‘NH). Mass spectrum (RX,70 eV): found n$e = 205.0129, calculated for C~HttN~~Se: 205.0118. Titration with 0.1 N NaOH in water containing 0.162 M KN03 revealed that the equivalent weight of the sample prepared was 99.8% of the theoretical value. The pKa values calculated from the titration curve are indicated in table 1. Results of elemental analysis were within 0.4 % of the theoretical value for C, H and N.
Histamine Hz_activity was determined on the isolated spontaneously beating guinea pig right atrium acconiing to Sterk et aL5 The pDz values were derived from the 50% level of the maximum response of the agonistic doseresponse curves. Affvrity to the %-receptor was determined on rat histamine Hz-receptors expressed in CHO cell as described by Traiffort et al6 using [ 12sIJ-i~oa~no~tentidine
as the ~ioligan~
the dispIacement
curves were analysed with the program LIGAND’. Amsela~e
(2b) behaves as a full agonist with a pD2 value of 6.41 which makes it slightly more potent than
histamine and amthamine (ta). Its H2-agonistic character was verified with cimetkline as antagonist. Cimetidiie appeared to be a competitive antagonist with a pAZ value of 6.41 f 0.04 (3) with amselamine as agonist, which is in accordance with repotted values using other agonists2. Dose-response curves are shown in fig. 1.
1915
Amselamine, an Hz-receptor agonist
Table 1 Phamn~logical
data and basic@ of ~-agonists.
X
pD, f s.e.m’
2b
Se
8.41 f 0.06 (6)
2a
s
0.21 f 0.09 (7) 6.14 f 0.04 (22)
3.93 f 0.06 (3)
histamb
pKd f s.e.m.b
pK,, f 8.c.m C
pKa2 f s.e.m d
5.01 f 0.02 (3)
9.21 f 0.01 (4)
5.78 f 0.01 (4)
4.94 f 0.06 (3)
9.15 f 0.02 (6)
5.40 f 0.01 (6)
9.32 f 0.14 (3)
5.93 f 0.14 (3)
a Guinea pig right atrium; b. CHO rat Hg cells; c. aliihatic amine; d heterocyclic ring. Amselamine shows very wesk intemctio~~swith histamine HI- and H3-receptors. Thus concerning HI-activity
(guinea pig ileum) a p4-value
of 3.85 f 0.07 (4) against histamine was found, whereas in the test for Hs-
activity (electrically stimulated guinea pig jejunum)l a pDz-value of 4.44 f 0.05 (3) was established. These results make am&amine a selective and relatively potent histamine $-agonist. Fig. 1 Functional effects of amselamine on histamine %-receptors. (Guinea pig right atrium, chronotropic effect)
-9 o
-6
-7
-6
-5
-4
-3
Lo(([l
Histaminc. l Am&mine w Amselamine + 104 M Cimetidine and A Amselamine + lO_3 M Cimetidine.
Recently we provided evidences that monocations of histamine, dimaprit and a number of thiazoles exert their interaction with the histamine %-receptor
through H-bond formation with the primary ammonium group,
protonation of the aromatic N-atom and H-bond formation (if X = NH) or electrostatic interaction (if X = S) as
H.
1916
shown in fig. 2. Fig. 2
VAN DEB
GOOT et al.
Binding to the histaxnim H2-receptor
Since the selenazole ring of amsehmine is somewhat more basic than the thlazole ring of amthamlne (table 1). it may be expected that amselamlne has a slightly higher affinity for the H2-receptor than an&amine. However, since amthamlne and amselamine exert almost equal affinltiea for the histamine %-receptor on CHO cells, such a statistically significant higher affinity was not established.
It appeared that the seleno analogue of the potent histamine HTagonist amthamine, which is designated as amselamine. behaves as a potent histamine h-agonist with a higher potency than histamine itself. Moreover amselamine exerts hardly any activity for histamine Ht- and Hj-receptors, which makes it selective for the histamine q-receptor. Acknowledgement.The
research of Dr. R. Leurs has been made possible by a fellowship of the Royal
Netherlands Academy of Arts and Sciences.
1. Weinstein. H.; Chou, D.; Johnson, C.L.; Kang, S.; Green, J.P. Mol. Pharmacol. 1976.12.738. 2. Van der Goat, H.; Bast, A.; Timmerman, H. Handbook of Experimental Pharmacology; Uvnls, B., Ed.; 3. 4. 5. 6
Springer-Verlag: Berlin, 1991; Vol. 97, pp. 573 - 748. Exiks, J.C.; Van der Goot, H.; Timmerman, H. Mol. Pharmacol. 1993,44,886. Eriks. J.C.; Van der Goat, H.; Sterk, G.J.; Timmerman, H. J. Med. Chem. 1992.35, 3239. Sterk, G.J.; Van der Goat, H.; Tiierman, H. Eur. J. Med. Chem. 1984,19,545. Tralffort. E.; Ruat, M.; Arrang, J.M.; Leurs, R.; Pomelli, D.; Schwartz, J.C. Proc. Natl. Acad. Sci. 1992,
89, 2649. 7 Munson, P.J.; Rodbard, D. Anal. Biochem. 1980,107,220. 8. Vollinga, R.C.; Zuiderveld, O.P.; Scheerens. H.; Bast, A.; Timmexman. H. Meth. Find. Exp. Clin. Phannacol. 1992.14.747.
(Received in Belgium 3 March 1994; accepted 19 May 1994)