Antihypertensive activity of para-substituted clonidine analogues and their acylated derivatives.
| dc.contributor.author | Lewis, Martin (Alan) | |
| dc.date.accessioned | 2015-07-30T03:32:43Z | |
| dc.date.available | 2015-07-30T03:32:43Z | |
| dc.date.issued | 1994 | |
| dc.description.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. | en_US |
| dc.identifier.uri | http://hdl.handle.net/123456789/959 | |
| dc.language.iso | en | en_US |
| dc.subject | Clonidine Analogues | en_US |
| dc.subject | Acylated Derivatives. | en_US |
| dc.title | Antihypertensive activity of para-substituted clonidine analogues and their acylated derivatives. | en_US |
| dc.type | Thesis | en_US |
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