Antihypertensive activity of para-substituted clonidine analogues and their acylated derivatives.
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Date
1994
Authors
Lewis, Martin (Alan)
Journal Title
Journal ISSN
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Abstract
The use of clonidine in antihypertensive drug regimens
has been severely limited by tr.e appearance of
withdrawal hypertension upon, abrupt discontinuation of
treatment. It is not known if a separation of rebound
hypertension from hypotensive activity is possible
through structural alteration. The present
investigation involved a study of the effects of
p-substitution and N-acylation of clonidine on the
hypotensive potency, rebound hypertension and
a-adrenocepcor selectivity. The antihypertensive
activity and potential for exhibiting withdrawal
hypertension of eleven analogues were compared to
cronidine in Spontaneously Hypertensive Rats(SHRs).
Intraperitoneal ad~inistration at 56 nmol./kg over a
period of 20 days in the SHRs followed by abrupt
withdrawal did not re'Jeal significant antihypertensive
activity in any of the analogues except for AL-1.2.
During the withdrawal phase, the systolic blood
pressure of AL-1.2-treated rats did not show a rebound
increase or overshoot. The absence of rebound
hypertension was believed to be due to the isobutyryl
functional group in the para position. The role of
N-acylation was unclear. The intravenous
administration in pentobarbitone-anesthetized
nc:::-:-.0tens i ve rats revealed a lower hypotensive efficacy
in =omparison to clonidine. p-Substitution with
ni:~ile functional groups resulted in compounds with
al~:st no hypotensive activity while an appreciable
amc~nt of activity was retained in compounds with
p-s~bstitutions involving the hydroxylmethyl and
car~oethoxyl functional groups. In the same
ex~~riments in which heart rate was monitored,
N-a=ylation was more effective in reducing bradycardia
whe~ compared to p-substitution. In the rat
anc=0ccygeus preparation, it was observed that the
corr.;:>unds CL-1.1, CL-1.2, AL-1.0, AL-1.1 and AL-1.2
dis;~ayed weak a 1 -adrenoceptor stimulatory activity.
AL-~.2 had the lowest affinity for a 1 -adrenoceptors and
dis;:ayed auto1ntibition at highe:: doses. In the
isc:~:ed rat vas deferens which was used to assess
pres~ยท:-1aptic a 2 -adrenoceptor activity, it was obs_erved
tha~ for high a 2 -adrenoceptor agonist activity, the
para Dosition should be left unsubstituted. Further,
for ~~gh a 2 -affinity at least one i~idazolidine nitrogen
should be left unsubstituted.
Description
Keywords
Clonidine Analogues , Acylated Derivatives.