Clonidine analogs

Clonidine and other imidazoline compounds have also been shown to reduce muscle spasms by their central nervous system activity. Tizanidine is perhaps the most thoroughly studied clonidine analog. It is an agonist at a2-adrenergic receptors, but reduces spasticity at doses that result in significantly less hypotension than clonidine. 

Ernsberger, R, Giuliano, R., Willette, R.N., Reis, D.J. (1990) Role of imidazole receptors in the vasodepressor response to clonidine analogs in the rostral ventrolateral medulla. J Pharmacol Exp Ther 253 408 18. 

Similar conclusions could be derived from an investigation of antihypertensive clonidine analogs, with respect to their peripheral hypertensive side effects. For a series of clonidine-related imidazolines, log Papp values were determined in -octanol/buffer at pH 7.4, central antihypertensive activities C2s (molar doses that cause a 25% blood pressure decrease, intravenous application) in anesthesized rats, peripheral hypertensive activities C o (molar doses that cause a 60-mm Hg blood pressure increase, intravenous application) in pithed rats (i.e., rats without central nervous system control), binding affinities IC50ai to ai receptors (replacement of prazosin), and binding affinities IC50+ 10 a2 receptors (replacement of clonidine) [86,87],... 

Eqs. 181 and 182 correlate hypotensive and bradycardic activities of ttj-adrenergic clonidine analogs (44) [796, 797]. While no log P term was necessary for the ED20(bradycardia) values (eq. 181), it had to be included to describe ED2o(hypoten-sion) values by EDjo(bradycardia) values (eq. 182) [396]. 

Another example of a proper QSAR application is given in eqs. 183—185 (chapter 7.5), which describe the central antihypertensive and peripheral hypertensive activities of clonidine analogs. While no predictions for more active analogs can be derived, three most important conclusions can be drawn from these equations first, the analogs can be tested in simple in vitro systems instead of whole animal models, second, log P values around 1.5 are optimal for the central nervous system-mediated antihypertensive activity, and third, one cannot expect to separate the antihypertensive activity from the hypertensive side effect. 

XXXV lowers blood pressure In hypertensive rats mainly by a peripheral mechanism. 34 y bbott 41596 (XXXVl), the best of a series of amino acid amides of dopamine, causes renal vasodilation of 3 hours duration at 12 mg/kg p.o. In dogsl It will be tested clinically for potential prophylactic use In hypertension and In renal diseases. A series of phosphodiesterase inhibitors from Merck show cardiostimulant, bronchodilator and hypotensive properties In animals. In this series, compound XXXVII shows good hypotension at doses that show no cardiac stimulation. The clonidine analog XXXVIII is active at 0.5 mg/kg p.o. in renal hypertensive... 

Figure 12. Chemical structure of clonidine (St 155) and the 2,6-diethyl-analog (St 91)...

A second hypothesis to explain the cardiovascular effects of clonidine involves an interaction with imidazoline-1 receptors (Bousquet and Feldman 1999). However, the available evidence at present does not prove conclusively the imidazoline hypothesis for the mechanism of action of clonidine and analog drugs, like rilmeni-dine and moxonidine (Szabo 2002). 

Figure 2.8 Clonidine 23 was designed as a nasal decongestant but it turned out to be a potent antihypertensive drug. Clinical tests revealed the antidepressant activity of iproniazid 24, an isopropyl analog of the antituberculosis drug isoniazid 25. D-Penicillamine 26 was originally used to treat Wilson s disease, to eliminate an excess of copper ions later it was recognized to have beneficial effects in rheumatoid arthritis.

Figure 10.8. Effect of cAMP on insulin secretion in pancreatic islet cells, a Stracture of the membrane-permeant analog dibutyryl-cAMP. The two butyryl groups and the acetyl group will be cleaved intracellularly, releasing cAMP. b Glucose-de-pendent insulin secretion in the presence or absence of dibutyryl-cAMP. cAMP amplifies glucose-dependent secretion, c Suppression of cAMP-mediated stimulation of insulin secretion by the a2-agonist clonidine. (Data from Life Sci. 32 191-95,1983.)...

FIGURE 16.5 Open analogs of clonidine (the hypotensive activity is expressed as variation of the arterial blood pressure 30 min after i.v. injection in pentobarbital anesthetized rats). ... 

Open analogs of the centrally acting hypotensive agent clonidine (Figure 16.5) have a similar activity profile but with a 30 to 100-fold loss in potency. Surprisingly seco-clonidine that is the closest analog of clonidine, was found to be less active than the corresponding monomethyl derivative. 

The antihypertensive imidazoline clonidine (Figure 20.4 R1 = R2 = Cl) and its analogs activate norepinephrine... 

Tiamenidine, N-(2-Chloro 4-methyl-3-thitnyl)-4,5-dihydro-1 H-imidazot-2-amine 2-1(2 -chloro -4 -methyl -3-thienyl)amino]-2-imidazoline 2-chloro-4-methyl-3-(2 -imidazolin-2 -y]amino)thiophene- C,HwCINjS mol wt 215.70. C 44.55%, H 4.67%, Cl 16.43%, N 19.48%, S 14.86%. A thiophene analog of clonidine, q.v. Prepn R. 

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