Nonpeptide angiotensin II receptor antagonists.

Substantial progress has been made recently in the development of nonpeptide angiotensin II receptor antagonists, a goal that has long remained an unmet challenge. Pieter Timmermans and colleagues review the pharmacology and the course of events that led to the identification of the lead compound and clinical candidate DuP753. Nonpeptide angiotensin II receptor antagonists represent novel therapeutic agents and are the preferred probes for exploring the (patho)physiological role(s) of angiotensin II. In addition, these compounds have provided evidence for the existence of different binding sites/receptors for angiotensin II.

Angiotensin II receptor antagonists and receptor subtypes.

Recently discovered nonpeptide angiotensin II receptor antagonists represent a new class of potential drugs for the treatment of hypertension and congestive heart failure. Further, these antagonists have been successfully used as selective research tools for physiologic studies of angiotensin H and defining angiotensin II receptor subtypes.

Effect of blocking angiotensin II receptor subtype on rat sympathetic nerve function.

This study examined effects of nonpeptide angiotensin II (Ang II) receptor subtype antagonists on the interaction of sympathetic function and Ang II in pithed rats. Effects of spinal cord stimulation (0.5-4 Hz) and norepinephrine (0.3-3 micrograms/kg i.v.) on mean arterial pressure (recorded with a carotid arterial catheter), cardiac output (measured with an electromagnetic flowmeter and flow probe around the thoracic ascending aorta), total peripheral resistance, and heart rate were determined. The subtype 1-selective Ang II receptor antagonist losartan (previously known as DuP 753) at 10 mg/kg i.v. blocked the hemodynamic responses to Ang II at 1 microgram/kg i.v. It inhibited mean arterial pressure and total peripheral resistance responses but not cardiac output and heart rate responses to spinal cord stimulation. In contrast, it reduced mean arterial pressure and cardiac output responses but not total peripheral resistance and heart rate responses to intravenous norepinephrine. Given at 100 mg/kg i.v., the subtype 2-selective receptor antagonist PD123177 did not reduce hemodynamic responses to intravenous Ang II, spinal cord stimulation, and intravenous norepinephrine. These results suggest that endogenous Ang II facilitates the release of norepinephrine from sympathetic nerve terminals in the vasculature of pithed rats. Similar to the Ang II receptor in vascular smooth muscle, the prejunctional Ang II receptor in pithed rats appears to be of subtype 1.

Effect of angiotensin II antagonism on canine renal sympathetic nerve function.

The objective of this study was to examine effects of nonpeptide angiotensin II (Ang II) receptor antagonists on renal vasoconstrictor responses to renal nerve stimulation (RNS) and intrarenal injection of norepinephrine in pentobarbital-anesthetized dogs. The subtype 1-selective Ang II receptor antagonists, DuP 753 (2-n-butyl-4-chloro-5-(hydroxymethyl)-1-[(2'-(1H- tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt) and EXP3174 (2-n-butyl-4-chloro-1-[(2'-(1H-tetrazol-5-yl) biphenyl-4-yl)methyl]imidazole-5-carboxylic acid) given intra-arterially to the kidney caused dose-dependent reductions of renal vasoconstrictor responses to RNS but not to norepinephrine. In contrast, the subtype 2-selective Ang II receptor specific ligand, PD 123177 (1-[(4-amino-3-methylphenyl)methyl]-5-(diphenylacetyl)-4,5,6,7- tetrahydro-1H-imidazo[4,5-c]pyridine-6-carboxylic acid), did not alter the renal vasoconstrictor responses to RNS, norepinephrine, and Ang II in doses of 10-100 micrograms/kg/min i.a. Captopril also reduced the renal vasoconstrictor responses to RNS but not to norepinephrine. However, saralasin did not alter the renal vasoconstrictor responses to RNS and norepinephrine, although it was as effective as DuP 753 and EXP3174 in blocking the renal vasoconstrictor response to Ang II. These results suggest that endogenous Ang II enhances renal adrenergic function at the prejunctional site in anesthetized dogs. Analogous to the Ang II receptor in vascular smooth muscle, the prejunctional Ang II receptor appears to be of subtype 1. Mechanisms accounting for the absence of the inhibition of Ang II-mediated renal adrenergic response by saralasin remain to be determined.

The hypotensive activity and side effects of methyldopa, clonidine, and guanfacine.

Clonidine (Catapres, Catapresan), guanfacine (Estulic), and methyldopa (Aldomet) are the prototypes of centrally acting antihypertensive drugs. Clonidine and guanfacine are lipophilic drugs that readily penetrate into the brain, where they stimulate alpha-adrenergic receptors in the pontomedullary region. The stimulation of these central alpha-adrenergic receptors has been shown to activate an inhibiting neuron, which causes a reduction of peripheral sympathetic tone and a subsequent fall in arterial blood pressure and heart rate. Both a centrally initiated reduction of vagus reflex activity and the activation of presynaptic alpha 2-adrenergic blocking agents in the heart may contribute to the bradycardia. Studies indicate that methyldopa also penetrates into the brain, where it is converted into alpha-methylnorepinephrine. This amine may stimulate the same central alpha-adrenergic receptors as those activated by clonidine, which will result in a hypotensive effect. Possibly, alpha-methyldopamine might also play a role. Accordingly, the modes of action of clonidine and alpha-methyldopa probably are very similar at a basic level. The central adrenergic receptors probably are located postsynaptically. Their receptor demand corresponds more closely to that of the alpha 2-subtype. Central alpha 1-adrenergic receptors might possibly play a part in the modulation of vagally induced baroreflex bradycardia. A discussion on the pharmacological basis of the side effects of the centrally acting antihypertensives has been limited to those adverse reactions that are somehow related to alpha-adrenergic receptors. Sedation, a common side effect, appears to be mediated by central alpha 2-adrenergic receptors, at least in animal models.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacology of calcium entry blockers: interaction with vascular alpha-adrenoceptors.

The pharmacology of calcium entry blockers (CEB), as used in various types of cardiovascular disease, is reviewed. Their vasodilator potency is analyzed, which is the most common therapeutic characteristic of all CEB, apart from the antiarrhythmic activity of verapamil. All CEB relax vascular smooth muscle, particularly in arteriolar beds, thus reducing peripheral vascular resistance. Arteriolar relaxation appears to be associated with inhibition of transmembrane calcium influx. Recent studies have demonstrated that vasoconstriction induced by stimulation of vascular postsynaptic alpha 2-adrenoceptors, using selective agonists, is reduced by CEB through a noncompetitive mechanism. However, vasoconstriction evoked by selective excitation of vascular alpha 1-adrenoceptors remains virtually uninfluenced by CEB. The selective interference of CEB with alpha 2-adrenoceptor stimulation suggests that calcium movement is associated with alpha 2-adrenoceptor stimulation. This mechanism may further contribute to the vasodilator effect of CEB by inhibiting that part of vascular tone evoked by the stimulation of alpha 2-adrenoceptors by endogenous catecholamines.

Effect of a monoclonal antibody to angiotensin II on hemodynamic responses to noradrenergic stimulation in pithed rats.

A specific angiotensin II monoclonal antibody, KAA8, was used to examine the interaction between sympathetic function and angiotensin II in pithed rats. KAA8, at 5 or 50 mg/kg i.v., did not alter the mean blood pressure, cardiac output, total peripheral resistance, or heart rate responses to sympathetic neural stimulation (0.25-4.0 Hz) or to norepinephrine (0.3-3 micrograms/kg i.v.) but blocked significantly the hemodynamic responses to angiotensin II (0.03-1.0 microgram/kg i.v.) and to angiotensin III (0.3-10 micrograms/kg i.v.). KAA8 treatment also reduced the plasma immunoreactive angiotensin II from 2,880 +/- 475 pg/ml to an undetectable level. In contrast, captopril (5 mg/kg i.v.) and saralasin (10 or 50 micrograms/kg/min i.v.) inhibited the mean blood pressure and total peripheral resistance responses, but not the cardiac output and heart rate responses, to sympathetic neural stimulation and to norepinephrine. These results, which confirm previous findings by Kaufman and Vollmer (Kaufman LJ, Vollmer RR: Endogenous angiotensin II facilitates sympathetically mediated hemodynamic responses in pithed rats. J Pharmacol Exp Ther 1985;235:128-134), demonstrate that angiotensin II selectively potentiates the sympathetic vascular function in the pithed rat. However, our results suggest that circulating angiotensin II does not appear to interact with the sympathetic vascular function. It is speculated that in the pithed rat the sympathetic vascular response is enhanced by vascular-formed angiotensin II.

Nonpeptide angiotensin II receptor antagonists. Studies with EXP9270 and DuP 753.

A series of nonpeptide angiotensin II (Ang II) receptor antagonists was evaluated in rat adrenal cortical microsomes for their inhibitory effects on the specific binding of [3H]Ang II, in the isolated rabbit aorta bioassay for their functional antagonism of contractile response to Ang II, and in high renin, renal-hypertensive rats for their intravenous antihypertensive effects, expressed as IC50, pA2, and intravenous ED30, respectively. Highly significant linear correlations were found between IC50 and pA2 (r = -0.88), between IC50 and intravenous ED30 (r = 0.79), and between pA2 and intravenous ED30 (r = -0.93). In both in vitro and in vivo functional assays, none of these antagonists exhibited agonistic effects. The orally active nonpeptide Ang II receptor antagonists EXP9270 and DuP 753 (oral ED30 = 3.6 and 0.59 mg/kg, respectively) were selected for further characterization. These antagonists exhibited selective and competitive Ang II antagonism in rabbit aorta and guinea pig ileum. In conscious normotensive rats, DuP 753 abolished the pressor response to saralasin, suggesting that the pressor effect of saralasin is attributed to its Ang II-like activity. In addition, DuP 753 also blocked the Ang II-induced drinking response and aldosterone release in rats. These results suggest that Ang II receptor blockade is the primary mechanism of the antihypertensive effect of these nonpeptide Ang II receptor antagonists. Further, the specificity and lack of partial agonistic effects of these molecules make them potentially useful physiological probes and therapeutic agents.

Hypotensive action of DuP 753, an angiotensin II antagonist, in spontaneously hypertensive rats. Nonpeptide angiotensin II receptor antagonists: X.

In conscious 18-21-week-old spontaneously hypertensive rats, DuP 753, a nonpeptide angiotensin II receptor antagonist, given orally at 3 and 10 mg/kg or intravenously at 3, 10, and 30 mg/kg, reduced blood pressure dose dependently. It did not alter heart rate at these doses. At 10 mg/kg i.v., DuP 753 decreased blood pressure significantly for at least 24 hours, suggesting a long duration of the antihypertensive effect. Unlike saralasin, DuP 753 did not cause a transient increase in blood pressure. The acute antihypertensive efficacy of DuP 753 was greater than that of captopril. Our data indicate that, for captopril to reduce blood pressure to a similar extent as that of DuP 753, it would need to be supplemented by a diuretic. DuP 753 did not have an acute diuretic effect. Bilateral nephrectomy, but not inhibition of prostaglandin synthesis, abolished the antihypertensive effect of DuP 753, suggesting that the antihypertensive effect of DuP 753 is dependent on an active renin-angiotensin system. Furthermore, DuP 753 inhibited the pressor response to angiotensin II but not the responses to norepinephrine, vasopressin, and Bay K 8644 (a calcium agonist). As neither DuP 753 nor captopril decreased blood pressure acutely in Wistar-Kyoto normotensive rats, our results suggest that the renin-angiotensin system plays a significant role in the control of blood pressure in spontaneously hypertensive rats.

Nonpeptide angiotensin II receptor antagonists. IV. EXP6155 and EXP6803.

EXP6155 (2-n-butyl-1-[4-carboxybenzyl]-4-chloroimidazole-5-acetic acid) and EXP6803 (methyl 2-n-butyl-1-[4-(2-carboxybenzamido)benzyl]-4-chloroimidazole -5-acetate, sodium salt) are shown to be novel, nonpeptide, antihypertensive, specific angiotensin II receptor antagonists. In rabbit aorta, they competitively inhibited the contractile response to angiotensin II with pA2 values of 6.54 and 7.20 and did not alter the response to norepinephrine or KCl. In guinea pig ileum, both agents blocked the responses to angiotensin I and II and did not alter the responses to bradykinin and acetylcholine. A similar specific angiotensin II antagonism was shown in vivo in the spinal pithed rat model. In renal artery-ligated rats, a high renin hypertensive model, EXP6155 and EXP6803 given intravenously, decreased blood pressure with ED30 of 10 and 11 mg/kg, respectively. Both compounds did not alter blood pressure when given orally at 100 mg/kg. Unlike saralasin, EXP6155 and EXP6803 given intravenously did not cause a transient increase in blood pressure in the renal artery-ligated and normotensive rats. Our results indicate that EXP6155 and EXP6803 are selective angiotensin II receptor antagonists and antihypertensive agents. Since neither compound had partial agonist activities or bradykinin potentiation effects, unlike the existing peptide angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, respectively, they may represent preferred probes for studying the physiological roles of angiotensin II.

Angiotensin II receptor antagonists. From discovery to antihypertensive drugs.

Some simple N-benzylimidazoles, originally described by Takeda Chemical Industries (Osaka, Japan), were characterized to be very weak but selective nonpeptide angiotensin II (Ang II) receptor antagonists with a competitive mode of action. Chemical modifications of these led to EXP6155 and EXP6803, which showed approximately 10- and 100-fold higher affinity, respectively, but were orally ineffective. Oral activity was obtained for the biphenyl carboxylic acid derivatives EXP7711 and especially EXP9654. A further advance in the design of nonpeptide Ang II receptor antagonists was provided by DuP 753, an analogue of EXP7711 in which the carboxylic acid function is replaced by its tetrazol-5-yl equivalent. DuP 753 (2-n-butyl-4-chloro-5-hydroxymethyl-1-[(2'-(1H-tetrazol-5-yl)bi phe nyl-4- yl)methyl]imidazole, potassium salt) displaces radiolabeled Ang II from its specific binding sites in various tissues, affording IC50 values of approximately 20 nM. DuP 753 competitively antagonizes Ang II-induced responses in various in vitro and in vivo preparations but does not influence those to KCl, norepinephrine, vasopressin, and others, nor does it affect converting enzyme and renin. In high renin animal models of elevated arterial blood pressure, intravenous and oral administrations of DuP 753 produce a sustained decrease in pressure without influencing heart rate. Marked antihypertensive effects are observed in spontaneously hypertensive rats, but no efficacy is noticed in deoxycorticosterone acetate hypertensive animals. DuP 753 showed no agonistic properties in any of the above test systems and has been chosen to undergo clinical trials for the treatment of hypertension. In rats, the 5-carboxylic acid (EXP3174) represents a major metabolite of DuP 753.(ABSTRACT TRUNCATED AT 250 WORDS)

Role of alpha adrenoceptors in hypertension and in antihypertensive drug treatment.

Recent plethysmographic experiments suggest that both postsynaptic alpha 1 and alpha 2 adrenoceptors in human resistance vessels play an important role in the maintenance and regulation of vascular tone. Central alpha 2 adrenoceptors are assumed to be involved in the central regulation of blood pressure. Radioligand binding studies on the density and characteristics of alpha adrenoceptors have not revealed consistent differences between normotensive and hypertensive subjects, with the exception of pheochromocytoma, in which a consistent down regulation of alpha 2 adrenoceptors in thrombocytes has been demonstrated. The radioligand binding studies are limited, since they cannot be performed on vascular tissues. Alpha adrenoceptors are vitally important as targets of several antihypertensive drugs; the activities of these agents and the principles and clinical relevance of mechanisms involving alpha adrenoceptors are reviewed.

Specific binding of threo 1-(1-[2-(1,4-benzodioxane-2-yl)-2-hydroxyethyl]4-piperidyl)-2-benzimidazolinone (R 29814), to rat brain membranes.

The binding of 3[H]R 29814, the pharmacologically less active threoisomer of the potent hypotensive agent erythro-R 28935, was assayed in rat brain membranes and compared with published data on 3[H]R 28935 binding. The 3[H]R 29814 bound to homogenates of rat brain with one saturable component with high affinity (KD = 1.1 nM). The specific binding was rapid and reversible. It was not affected by sodium or magnesium ions, or by guanosine triphosphate. The maximum number of binding sites amounted to approximately 135 fmol/mg protein. The drug specificity of the 3[H]R 29814 binding site was not associated with that of any known drug recognition site, but corresponded to that of erythro 3[H]R 28935. A linear relationship was derived between the affinities of drugs for inhibiting 3[H]R 29814 and 3[H]R 28935 binding. The results suggest that identical sites were labeled by 3[H]R 29814 and 3[H]R 28935 in rat brain membranes with comparable affinity. Since the hypotensive activities of R 29814 and R 28935 greatly differ, it is concluded that the high affinity binding sites of 3[H]R 29814 as well as those of 3[H]R 28935 are not compatible with the sites responsible for the hypotensive effect.

Control of blood pressure and end-organ damage in maturing salt-loaded stroke-prone spontaneously hypertensive rats by oral angiotensin II receptor blockade.

OBJECTIVE: To study the effects of renin-angiotensin system blockade by a novel non-peptide angiotensin II receptor antagonist, losartan, on development of hypertension and acceleration of end-organ damage in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP). DESIGN AND METHODS: One hundred and eighty-one male SHRSP were fed a 4% sodium diet from 6 to 18 weeks of age. Seventy-eight SHRSP were treated orally with losartan, 30 mg/kg per day. One hundred and three rats constituted untreated controls. Blood pressure, plasma renin activity (PRA), renal function and end-organ damage were monitored during the transition to malignant hypertension. RESULTS: Losartan prevented a blood pressure rise during the first 4 weeks of salt loading. Thereafter, blood pressure rose slowly in losartan-treated rats; however, at each time-point studied blood pressure was significantly lower in losartan-treated rats than in control rats. Losartan treatment increased PRA during the first 4 weeks, but this effect was not sustained. Thereafter, PRA decreased to control (week 0) levels. In contrast, 2 weeks after high-sodium feeding started, untreated SHRSP failed to suppress PRA appropriately; thereafter, PRA rose significantly. Losartan affected renal pathophysiology by blunting the decline in glomerular filtration rate, controlling proteinuria and preventing or delaying the appearance of malignant nephrosclerosis. Losartan treatment significantly increased survival and completely prevented cerebrovascular infarcts. CONCLUSIONS: The results indicate that angiotensin II blockade markedly reduces both hypertension and end-organ damage in chronically salt-loaded SHRSP and that the renin-angiotensin system may play an important role in the development of hypertensive cardiovascular disease in SHRSP.

Angiotensin II receptor antagonist delays renal damage and stroke in salt-loaded Dahl salt-sensitive rats.

OBJECTIVE: To study the effects of blockade of the renin-angiotensin system upon the development of hypertension, end-organ damage and mortality in Dahl salt-sensitive (DSS) rats using an angiotensin II receptor antagonist, losartan. DESIGN AND METHODS: DSS rats (n = 186) were fed 8% NaCl from 6 to 16 weeks of age. One group received losartan whilst the control group was untreated. Changes in blood pressure and plasma renin activity (PRA), as well as renal and cerebrovascular damage and survival were assessed during the study. RESULTS: Losartan blunted the blood pressure rise only transiently. Salt loading suppressed PRA in both groups until week 4 and thereafter it rose more markedly in the treated group. With no treatment renal lesions were first detected at 2 weeks, and strokes at 6 weeks. However, losartan transiently decreased the incidence and delayed the progression of renal damage and cerebrovascular lesions (strokes) and increased survival. PRA correlated with renal damage and the incidence of strokes in both groups. Blood pressure only partially affected survival, but did not correlate with stroke incidence. CONCLUSIONS: These results indicate that whereas the rise in blood pressure is dependent upon sodium loading, morbidity and mortality in salt-loaded DSS rats are associated with activation of the renin-angiotensin system and are only partially related to blood pressure.

Quantitative structure-activity relationships in centrally acting imidazolidines structurally related to clonidine.

The central hypotensive action of clonidine and 26 structurally related derivatives was quantified by means of an ED30 obtained from dose-response curves following intravenous administration to anesthetized, normotensive rats. Multiple regression analyses of the biological data yielded correlation equations comprising a relationship between hypotensive activity and molecular structure. In the equations the pharmacokinetics together with the actual engagement of the central alpha-adrenoceptor are accounted for. More detailed characteristics of this central alpha-adrenoceptor emerged from correlation studies in which new ED30 values, associated with brain concentrations, were employed. The use of this biological parameter at the alpha-adrenoceptor level allowed the presentation of a hypothetical working model for the mechanism of interaction between this receptive site and clonidine-like imidazolidines.

Accumulation of drugs by guinea pig isolated atria. Quantitative correlations.

The time course of the tissue accumulation of 16 neutral, cationic, and anionic drugs by resting and 2-Hz stimulated atria of the guinea pig was measured. The accumulation of the substances was quantified by means of their tissue to medium ratios (T/M). Auricles driven with 2 Hz accumulated the drugs faster and during a long period of time to a greater extent than resting atria. By extrapolation of the binding characteristics, the final equilibrium T/M values were estimated. The variance in these accumulation data at equilibrium (log T/M) Could be best described by a linear combination of log P (octanol/water) and the ability of the drugs to bind to atrial homogenate (log percent bound/percent free). A parameter calculated from protein binding appeared less significant. Comparable results were obtained for the accumulation data measured in resting and 2-Hz stimulated atrial muscles. It is suggested that the degree of accumulation of drugs into atrial tissue is determined by the facility of their penetration of the plasma membrane and the extent of their intracellular binding.

A novel series of selective, non-peptide inhibitors of angiotensin II binding to the AT2 site.

The availability of peptide and non-peptide Ang II receptor antagonists has permitted the study of Ang II receptor heterogeneity. It is now widely recognized that there are at least two distinct Ang II receptor subtypes. AT1 receptors are selective in their recognition of agents such as losartan, DuP 532, L-158,809, SK&F108566, and similar non-peptides. To date, all of the well-known actions of Ang II in mammals are blocked by the AT1 selective antagonists such as losartan and are thus designated as being mediated by the AT1 receptor. Although there have been reports of functional activity mediated through AT2 sites, the pharmacological role for the AT2 receptor has not yet been elucidated. Herein, we report the chemistry and SAR on a novel series of 1,2,3,4-tetrahydrosioquinoline-3-carboxylic acids which have selective affinity for AT2 receptors. The most potent of which (19) has an IC50 of 30 nM for the AT2 receptor in the rat adrenal radioligand binding assay.

Balanced AT1/AT2 receptor antagonists. 4. XR510 and related 5-(3-amidopropanoyl)imidazoles possessing equal affinity for the AT1 and AT2 receptors.

The identification of the AT1 and AT2 receptor subtypes has stimulated interest in developing balanced angiotensin II receptor antagonists. A series of 5-(3-amidopropanoyl)imidazoles has been prepared which possess balanced affinity for the AT1 and AT2 receptors. XR510 (1), 1-[[2'-[[(isopentoxycarbonyl)amino]sulfonyl]-3- fluoro(1,1'-biphenyl)-4-yl]methyl]-5-[3-(N-pyridin-3- ylbutanamido)propanoyl]-4-ethyl-2-propyl-1H-imidazole, potassium salt, exhibits subnanomolar affinity for both receptor sites. XR510 is very active in lowering blood pressure in renal hypertensive rats and furosemide-treated dogs following oral administration.

Quantitative relationships between alpha-adrenergic activity and binding affinity of alpha-adrenoceptor agonists and antagonists.

Quantitative relationships between in vitro affinity for alpha 1- and alpha 2-adrenoceptors (specific binding sites in rat brain membranes of [3H]prazosin and [3H]clonidine, respectively) and in vitro and in vivo alpha 1/alpha 2-adrenoceptor agonist/antagonist activities were derived for a series of 11 alpha-adrenergic antagonists and 35 agonists of dissimilar chemical structure. For the antagonists, the alpha 1/alpha 2-binding selectivity ratio most significantly correlated with the functional alpha 1/alpha 2-blocking selectivity ratios assessed in vitro (rabbit isolated pulmonary artery: antagonism of alpha 1-adrenoceptor-induced vasoconstriction and alpha 2-adrenoceptor-evoked facilitation of transmitter release) and in vivo (antagonism of alpha 1- and alpha 2-adrenoceptor-mediated vasoconstriction in pithed normotensive rats). These results show that the in vitro alpha 1- and alpha 2-adrenoceptor binding affinities of the antagonists provide adequate information concerning their functional alpha 1- and alpha 2-adrenoceptor blocking potencies against agonists. For the agonists, the central, alpha 2-adrenoceptor-elicited, hypotensive activity was not correlated with alpha 1-adrenoceptor binding affinity but was most significantly described in terms of affinity for alpha 2-adrenoceptors and a parabolic dependence on log P' (octanol/buffer; pH 7.4; 37 degrees C). The relevance of log P' in the regression is explained by the difference in accessibility to the membrane-bound alpha 2-adrenoceptors in the radioligand displacement experiments and the central medullary (hypotensive) alpha 2-adrenoceptors in the intact animal. In contrast, the affinity parameters for alpha 1- and alpha 2-adrenoceptors were found to be poor descriptors of the hypertensive potency of the agonists in which alpha 1- and alpha 2-adrenoceptors are known to play a role. The correlations in which the individual binding parameters and the combination of both variables were included reached only a moderate significance level.(ABSTRACT TRUNCATED AT 250 WORDS)