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On the selectivity of in vitro inhibition of rat colon motility by β-adrenergic substituted phenylethanolamines
European Journal of Pharmacology, 187 (1990) 563 Elsevier
563
EJP 20718
Erratum X l t h I n t e r n a t i o n a l Congress of P h a r m a c o l o g y ( A m s t e r d a m , The Netherlands), Brief C o m m u n i c a t i o n s , ( F r i d a y 6 July, 1990), E u r o p e a n J. Pharmacol. 183 (1990) 2197-2198.
On the selectivity of in vitro inhibition of rat colon motility by/3-adrenergic substituted phenylethanolamines M a n a r a , L., Guzzi, U., Aureggi, G., Croci, T., Bianchetti, A. Groupe Sanofi, Midy S.p.A. Research Center, Via Piranesi 38, Milan, Italy Our new gut-specific phenylethanolaminotetralines (PEAT) inhibit the motility of rat proximal colon in vitro presumably by stimulation of atypical fl-adrenoceptors (Manara et al., 1989). Other investigators reported that lipolytic fl-adrenoceptor agonists structurally related to PEAT such as BRL 37344 and its corresponding methyl ester BRL35135A, relaxed chemically contracted guinea-pig ileum (Bond and Clarke, 1988) and gastric fundus (Coleman et al., 1987) by acting on apparently similar atypical fl-adrenoceptors. We synthetized BRL35135A and BRL37344 (compounds Ia and Ib, Table 1) and Ic and compared them with isoprenaline and the corresponding racemates of two representive PEAT esters, IIa and IIb, in the following isolated preparations: longitudinal segments of rat proximal colon (inhibition of spontaneous phasic contractions), guinea-pig right atria (increase of frequency, a fll effect) and rat uteri (inhibition of spontaneous contractions, a 132 effect). Compounds Ia, Ib and Ic, weakly active on guinea-pig atria, were potent inhibitors of rat colon and uterus motility. PEAT esters IIa and lib, inactive on guinea-pig atria, had less potency on colon than the racemates Ia and Ic, but had substantially greater colon-to-uterus selectivity. These results indicate that the PEAT, whose inhibition of rat colon motility is competitively antagonized by alprenolol and propranolol (Manara et al., 1989), are more gut-specific than the BRL compounds tested apparently because of greater selectivity towards atypical fl-adrenoceptors. Table 1 In vitro actions of substituted phenylethanolamines OH
W c1
I: X = CH3, Y = H; alkoxy chain in 4 II: X = Y = CH2CH2; alkoxy chain in 7 Isomers Colon Uterus EC50, nM _+S.E.
Ia (BRL35135A)-HBr Ib (BRL37344) Ic (SR 58896)
CH 3 H CH 3
RR+SS RR+ SS RS+SR
0.4_+0.1 1.4_+0.1 3.8_+0.5
IIa (SR 58539R)-HCI lib (SR 58538B)-HCI ( + )-Isoprenaline
C2Hs C2H~
RR + SS RS+ SR
6.2 5:0.5 7.5 _+0.8 1.6_+0.2
2.0_+0.2 15 _+3.8 31_+5.5 235 -+25 400_+76 0.36_+0.1
Atrium 1606_+246 2633 0-470 2100_+387 > 30000 > 30000 7.5+0.5
ECso = conc. producing half-maximal effect References
Bond, R. and Clarke, D., 1988, Br. J. Pharmacol., 95, 723. Coleman, R.A., Denyer, L.H. and Sheldrick, K.E., 1987, Br. J. Pharmacol., 90, 40P. Manara, L., Bianchetti, A., Croci, T. and Giudice, A., 1989, Neurochemical Pharmacology - A tribute to B.B. Brodie, E. Costa ed., Raven Press, 131.
563
EJP 20718
Erratum X l t h I n t e r n a t i o n a l Congress of P h a r m a c o l o g y ( A m s t e r d a m , The Netherlands), Brief C o m m u n i c a t i o n s , ( F r i d a y 6 July, 1990), E u r o p e a n J. Pharmacol. 183 (1990) 2197-2198.
On the selectivity of in vitro inhibition of rat colon motility by/3-adrenergic substituted phenylethanolamines M a n a r a , L., Guzzi, U., Aureggi, G., Croci, T., Bianchetti, A. Groupe Sanofi, Midy S.p.A. Research Center, Via Piranesi 38, Milan, Italy Our new gut-specific phenylethanolaminotetralines (PEAT) inhibit the motility of rat proximal colon in vitro presumably by stimulation of atypical fl-adrenoceptors (Manara et al., 1989). Other investigators reported that lipolytic fl-adrenoceptor agonists structurally related to PEAT such as BRL 37344 and its corresponding methyl ester BRL35135A, relaxed chemically contracted guinea-pig ileum (Bond and Clarke, 1988) and gastric fundus (Coleman et al., 1987) by acting on apparently similar atypical fl-adrenoceptors. We synthetized BRL35135A and BRL37344 (compounds Ia and Ib, Table 1) and Ic and compared them with isoprenaline and the corresponding racemates of two representive PEAT esters, IIa and IIb, in the following isolated preparations: longitudinal segments of rat proximal colon (inhibition of spontaneous phasic contractions), guinea-pig right atria (increase of frequency, a fll effect) and rat uteri (inhibition of spontaneous contractions, a 132 effect). Compounds Ia, Ib and Ic, weakly active on guinea-pig atria, were potent inhibitors of rat colon and uterus motility. PEAT esters IIa and lib, inactive on guinea-pig atria, had less potency on colon than the racemates Ia and Ic, but had substantially greater colon-to-uterus selectivity. These results indicate that the PEAT, whose inhibition of rat colon motility is competitively antagonized by alprenolol and propranolol (Manara et al., 1989), are more gut-specific than the BRL compounds tested apparently because of greater selectivity towards atypical fl-adrenoceptors. Table 1 In vitro actions of substituted phenylethanolamines OH
W c1
I: X = CH3, Y = H; alkoxy chain in 4 II: X = Y = CH2CH2; alkoxy chain in 7 Isomers Colon Uterus EC50, nM _+S.E.
Ia (BRL35135A)-HBr Ib (BRL37344) Ic (SR 58896)
CH 3 H CH 3
RR+SS RR+ SS RS+SR
0.4_+0.1 1.4_+0.1 3.8_+0.5
IIa (SR 58539R)-HCI lib (SR 58538B)-HCI ( + )-Isoprenaline
C2Hs C2H~
RR + SS RS+ SR
6.2 5:0.5 7.5 _+0.8 1.6_+0.2
2.0_+0.2 15 _+3.8 31_+5.5 235 -+25 400_+76 0.36_+0.1
Atrium 1606_+246 2633 0-470 2100_+387 > 30000 > 30000 7.5+0.5
ECso = conc. producing half-maximal effect References
Bond, R. and Clarke, D., 1988, Br. J. Pharmacol., 95, 723. Coleman, R.A., Denyer, L.H. and Sheldrick, K.E., 1987, Br. J. Pharmacol., 90, 40P. Manara, L., Bianchetti, A., Croci, T. and Giudice, A., 1989, Neurochemical Pharmacology - A tribute to B.B. Brodie, E. Costa ed., Raven Press, 131.