Prazosin structure

Alfuzosin (91) is a prazosin-like hypotensive adrenergic a-1 receptor blocker with the special structural feature that two carbons have been excised conceptually from the piperazine ring normally present in this series. Following the usual sequence for this series, reaction of 4-amino-2-chloro-7-dimethoxyquinazoline (89) with the tetrahydro-2-furyl amide of 3-methylaminopropyla-mine (90) gives alfuzosin (91) [25], Alfuzosin is claimed to cause less orthostatic hypotention (dizziness or fainting upon sudden rising) than prazosin. 

Giardina, D., Gulini, U., Massi, M., Piloni, M.G., Pompei, P., Rafaiani, G. and Melchiorre, C. (1993) Structure-activity relationships in prazosin-related compounds. 2. Role of the piperazine ring on alpha-blocking activity. Journal of Medicinal Chemistry, 36, 690-698. 

Prazosin (see structure in Figure 12.2), the prototypic drug in this class, decreases peripheral vascular resistance in arterioles and veins by blocking alpha receptors on vascular smooth muscle. It does not decrease cardiac output. Because of this effect, patients taking prazosin are more prone ( 50 percent) to postural hypotension, particularly following the first dose. In some cases, the hypotension is so severe that the patient may lose consciousness. In an attempt to compensate, the baroreceptors may produce an accompanying tachycardia. 

Figure 10.10. Structures of a-receptor blockers. Phentolamine and tolazoline block both a,- and ct2-receptors, whereas prazosine selectively inhibits aj-receptors.

Terazosin Hydrochloride. Terazosin hydrochloride. I -l4-amino-f).7-dimethoxy-2-quinaz.olinyl)-4-(tetnihydro-2-fu-royllpipcrazinc monohydrochloride (Hytrin), is a structural congener of prazosin hydrochloride. It possesses similar selc-ctive properties of specincally inhibiting 0 -udrenergic receptors. The drug is slightly less potent than prazosin hydrochloride. Terazosin hydrochloride has a half-life of approximately 12 hours, which is much longer than that of prazosin. This lends itself to a once-daily dose to control hypertension in ntany patients. 

Doxazosin is a quinazoline and structurally related to prazosin (and therefore BODIPY FL-prazosin). In addition, YM12617 inhibits BODIPY FL-prazosin binding to rat anococcygeus smooth muscle (our unpublished observations, (1995 Fig 4). Therefore, it was of interest to examine the receptor distribution in isolated human prostate smooth muscle cells. We observed and quantified significant amounts of intracellular binding in these cells, and this was eliminated by the selective a1A-AR antagonist RS100329 (36,37), which is consistent with the belief held by some workers that a1A-ARs are located in mainly intracellular locations (9). 

Examples of ai-blockers include compounds of diverse structures, such as the synthetic heterocyclics prazosin, indoramin, phentolamine the ergot alkaloids crgotamine and dil droergotamine and the haloalkylamine irreversible alkylators, e.g. phenoxybenzamine. Examples of antagonists relatively selective for a2-receptors over a,-receptors, are the natural indolealkylamine alkaloid yohimbine and its diastereoisomer rauwoisdnc (though they also have affinity for 5-HT receptors). However, mariy of the tt -blockers (especially prazosin) also have some affinity at the a2-adrenoceptor site. 

TRIM (1-(2-trifluoromethylphenyl)imidazole) is a nitric OXIDE SYNTHASE INHIBITOR active on neuronal sites, and is used as a pharmacological tool, trimazosin (ban, inn] (trimazosin hydrochloride (usan]) contains a piperazinyl quinazolinyl nucleus and is similar to prazosin. It is an (tti-subtype) O-ADRENOCEPTOR antagonist with structure and actions. It is an ANTIHYPERTENSIVE, and can be used in combination with other drugs in heart FAaURE TREATMENT. 

Antihypertensive Vasodilators - Prazosin (Pfizer) has been introduced - -0 into the U.S. Unlike other vasodilators it causes a decrease in plasma renin levels.79 The use of hydralazine has been reviewed, and the structure-activity relations of hydrazinopyridazines and phthalazines have been studied using molecular orbital calculations8l and Hansch analysis. 2 Animal pharmacology has been summarised and the first clinical data reported83 for Lepetit 6150 (15 ). In 20 patients it was found to be 8 times... 

Figure 1. Design strategy for the synthesis of hybrid tetraamines by inserting the structural features of prazosin on the terminal nitrogens of the tetraamine backbone of benextramine.

The finding that the affinity profile of prazosin-related quinazolines can depend on the type of moiety linking the two nitrogen atoms of the piperazine ring of prazosin, prompted us to further modify the structure of analogue 2. In particular, two types of structural modifications were performed on the structure of 2, that is, replacement of the... 

Fig. 3. Design strategy for the synthesis of prazosin-related quinazolines by inserting a substituent on the furan ring of 2 or 3 or by replacing the furan ring of 2 with an (un)substituted phenyl ring. See Table 2 for structures.

Giardina, D., Brasili, L., Gregori, M.. Massi, M., Picchio, M.T., Quaglia, W., Melchiorre, C., 1989. Structure-activity relationships among prazosin-related compounds. Effect of piperazine ring replacement by an alkanediamine moiety on a,-adrenoreceptor blocking activity. J. Med. Chem. 32, 50-55. 

Doxazosin (CARDURA, others), a structural analog of prazosin, is a highly selective antagonist,... 

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