Alpha 1-adrenoceptor properties of terazosin HCl and its enantiomers in the human prostate and canine brain.

The objective of the present study was to characterize the alpha 1-adrenoceptor binding properties of terazosin and its enantiomers in human prostate and canine brain. Human prostate adenomas were obtained from 7 males undergoing prostatectomy for symptomatic BPH and canine cerebral cortices were obtained from 6 male beagles. Competitive displacement experiments were carried out on these tissue homogenates in the presence of a constant concentration ([180 pM]) of 125I-Heat and varying concentrations of unlabelled terazosin and its enantiomers. The Ki of terazosin and its enantiomers were determined from these binding studies. The mean Ki of rac-terazosin, R(+)-terazosin, and S(-)-terazosin in human prostate was 3.6 nM, 3.8 nM, and 2.8 nM, respectively. The differences between these mean Ki values were not statistically significant. The mean Ki of rac-terazosin, R(+)-terazosin, and S(-)-terazosin in canine brain were 6.7 nM, 8.4 nM, and 5.6 nM, respectively. The differences between these mean Ki values were not significantly different. The mean Ki of terazosin and its enantiomers were consistently lower in the human prostate compared to canine brain (P less than 0.05). The present study does not provide any evidence suggesting differential effects of terazosin enantiomers on the human prostate. The twofold difference between the Ki values in the prostate and brain suggests that different subtypes of the alpha 1-receptor might be present in these tissues.

Novel adrenergic compounds. I. Receptor interactions of ABBOTT-54741 [(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthtyl)imidazoline], an alpha-adrenergic agonist.

ABBOTT-54741 was identified as a full alpha-adrenergic agonist; its interaction with the alpha-adrenergic receptor was compared to that of norepinephrine. ABBOTT-54741 lacks affinity for beta-adrenergic receptors. In radioligand binding studies, the affinity of ABBOTT-54741 for alpha 1-adrenoceptors (as measured against 3H-prazosin binding) was KI = 401 nM, and that for norepinephrine was 388 nM. The affinity of ABBOTT-54741 for alpha 2-adrenoceptors (as measured against 3H-rauwolscine binding) was greater than that of norepinephrine (KIA = 7 nM; KI NE = 37 nM). In vitro, ABBOTT-54741 exhibits high potency in vascular preparations (ED50NE/ED50A in rabbit aorta = 12.9; in phenoxybenzamine-treated dog saphenous vein = 188.5). In rabbit pulmonary artery, it shows greater potency for the presynaptic than postsynaptic receptors, corroborating the observations of selectivity obtained in binding studies. The observations in vivo reflect that in isolated tissues. In different species (dog, rat) and via different routes of administration (i.v., p.o., i.c.v., and nasal), ABBOTT-54741 exhibits cardiovascular effects reflecting the stimulation of both alpha 1- and alpha 2-adrenoceptors consistently with much greater potency than norepinephrine or any other alpha agonist known to the authors.

Differentiation of alpha-adrenergic receptors using pharmacological evaluation and molecular modeling of selective adrenergic agents.

Subtypes of alpha adrenergic receptors were studied using selective adrenergic agonists. A-53693, A-54741, and related compounds were evaluated for their affinity for alpha receptor subtypes using radioligand binding techniques. Efficacy and potency were also evaluated using in vitro bioassays of alpha-1 receptors in rabbit aorta smooth muscle and alpha-2 receptors in the phenoxybenzamine-pretreated canine saphenous vein. Active and inactive compounds were then submitted for computer-assisted molecular modeling evaluation to ascertain the structural requirements for optimal potency and selectivity. Rigid catecholamines such as A-53693 display a high degree of selectivity for alpha-2 compared to alpha-1 receptors, probably because of the unique regions of space at the ligand binding site occupied by active compounds. Imidazolines such as A-54741 also interact with extremely high affinity and potency for alpha-2 receptors, and to a lesser extent at alpha-1 receptors. The spatial domains occupied by phenethylamines and imidazolines differ, each having unique regions of permissable space at alpha receptors. Compounds such as A-53693 and A-54741 are extremely useful probes of the molecular interactions of alpha agonistic compounds which will help in the design of even more selective drugs for alpha adrenergic receptors.

A new nasal decongestant, A-57219: a comparison with oxymetazoline.

2-(4-Amino-3,5-dichlorobenzyl)imidazoline hydrochloride (A-57219), has alpha 1-agonist/alpha 2-antagonist activity and was more effective and long-acting than oxymetazoline on canine nasal mucosa, in-vitro and in-vivo. Upon intranasal administration to dogs, the compound was devoid of systemic effects up to a concentration 1000 times that needed for local decongestant effect (1.65 micrograms, atomized from a 1 microgram mL-1 solution) suggesting limited mucosal absorption. After nasal administration to rats for 15 days at a concentration 1000 times greater than that required for nasal decongestion, no mucosal tissue toxicity or systemic effects were seen.

Conformationally defined adrenergic agents. 5. Resolution, absolute configuration, and pharmacological characterization of the enantiomers of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline: a potent agonist at alpha-adrenoceptors.

(+/-)-2-(5,6-Dimethoxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline has been resolved into its (+) and (-) enantiomers, and the absolute configuration was established by single-crystal X-ray diffraction studies. The more active isomer has been assigned the R absolute configuration. Cleavage of the respective (+)- and (-)-dimethyl ethers with boron tribromide provided the corresponding (+)- and (-)-2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthl)imidazoline hydrobromides and these were pharmacologically characterized. In various preparations, the R enantiomer has been shown to be an extremely potent alpha agonist with preferential activity at the alpha 2-adrenergic receptor.

Similarity of central and peripheral alpha-1 adrenoceptors in rat and rabbit.

In order to examine species and tissue differences in alpha 1 adrenoceptors, binding experiments were performed using 3H-prazosin and membrane homogenates of central nervous and peripheral tissues of rabbit (cortex and spleen), and rat (cortex, spleen, and liver). Saturation studies indicated one binding site for 3H-prazosin, with apparent log molar dissociation constants (pKD) ranging from 9.43 to 10.20. The rank orders of affinities of three competing antagonists (prazosin much greater than idazoxan greater than rauwolscine) and five agonists (cirazoline greater than clonidine approximately equal to (-)-norepinephrine greater than (-)-phenylephrine greater than (+)-norepinephrine) were typical of alpha 1 receptors in all tissues. There were small but significant differences in the mean affinities of rauwolscine, idazoxan and cirazoline among the five tissues. No significant differences in pseudo-Hill coefficients were observed among tissues, although agonist binding curves were shallow (.7 to .85) and prazosin competition curves were significantly steeper (greater than .85). Guanine nucleotide did not affect the position or slope of the (-)-norepinephrine competition profile in rat cortex. These results demonstrate a qualitative similarity among central and peripheral alpha 1 receptors of the rat and rabbit, with small differences observed between central and peripheral sites in both species.

Conformationally defined adrenergic agents. 4. 1-(aminomethyl)phthalans: synthesis and pharmacological consequences of the phthalan ring oxygen atom.

The synthesis of a series of 1-(aminomethyl)phthalans 1b is reported. The radioligand binding to alpha 1- and alpha 2-receptors and the in vitro pharmacology in alpha 1 (rabbit aorta) and alpha 2 (phenoxybenzamine-pretreated dog saphenous vein) tissues were determined and were compared to the activity of the corresponding 1-(aminomethyl)indans. The activity of this series of phthalans was found to be consistent with the electrostatic repulsion hypothesis that was used to design the parent indan (ERBCOP) compounds. The effect of the phthalan ring oxygenation was to somewhat improve alpha 1-receptor potency relative to the 6-ERBCOP indans without having a general effect on the alpha 2-receptor potency. We conclude from the overall pattern of activity that while the norepinephrine type beta-hydroxyl group may be beneficial for binding to the alpha 1-adrenoceptor, it is not required for strong binding to or full stimulation of the alpha 2-adrenergic receptor, provided that the conformational mobility associated with the phenylethylamine is restricted and maintained in a favorable conformation for receptor interaction.

Conformationally defined adrenergic agents. 3. Modifications to the carbocyclic ring of 5,6-dihydroxy-1-(2-imidazolinyl)tetralin: improved separation of alpha 1 and alpha 2 adrenergic activities.

A series of modifications to positions 1, 2, and 4 of the tetralin ring of 5,6-dihydroxy-1-(2-imidazolinyl)tetralin (1, A-54741) succeeded in improving the separation of the potent alpha 1 and alpha 2 adrenergic agonism observed for the parent compound 1. In particular 5,6-dihydroxy-4,4-dimethyl-1-(2-imidazolinyl)tetralin (7) was found to be a specific alpha 1 adrenergic agonist, and 7,8-dihydroxy-4-(2-imidazolinyl)chroman (2) was found to have improved alpha 2 adrenergic agonistic selectivity relative to the parent compound 1.

Pharmacology of terazosin.

Terazosin is a quinazoline antihypertensive agent that is chemically similar to prazosin. The saturated furan ring of terazosin distinguishes these two compounds. Terazosin (0.1 to 3.0 mg/kg) lowered blood pressure without increasing heart rate when given orally to spontaneously hypertensive rats. No tolerance was observed during five days of repeated oral administration. Although equally efficacious in spontaneously hypertensive rats as its congener prazosin, terazosin exhibited a more gradual onset of action than prazosin, a more uniform and linear dose-response curve, and a less variable duration of action. When administered intravenously to dogs, terazosin lowered blood pressure primarily by decreasing peripheral vascular resistance. Pretreatment with phenoxybenzamine but not with atropine or propranolol resulted in a greatly reduced hypotensive response to terazosin, demonstrating that this effect of terazosin is mediated by a sympatholytic mechanism of the alpha type. The nature of the alpha-blocking properties of terazosin was evaluated in vitro using both radioligand binding studies and functional tests in rabbit aorta and pulmonary artery. These studies demonstrated that terazosin is highly selective for alpha1 receptors. The affinity for alpha1 receptors was approximately one-third that of prazosin. Like prazosin, terazosin displayed minimal interaction with alpha2 receptors. Median lethal dose values in rats ranged from 0.255 to 0.270 g/kg for intravenous administration and from 5.5 to 6.0 g/kg, for oral administration. Oral administration of high doses of the compound to rats did not produce any gastrointestinal irritation and/or apparent abnormal behavioral effects. Comparison of the oral activity of terazosin in spontaneously hypertensive rats with the oral toxicity values in normal rats revealed a high efficacy/safety ratio. Terazosin given intravenously to rats and mice was 2.6 to 5.0 times less toxic than prazosin. The absorption of terazosin appeared to be slower than that of prazosin in rats. However, from eight to 16 hours after dosing, terazosin concentrations in plasma exceeded those of prazosin, suggesting the possibility of once-daily dosing with terazosin. In addition, terazosin exhibited statistically significant cholesterol lowering effects in gerbils.

Conformationally defined adrenergic agents. 2. Catechol imidazoline derivatives: biological effects at alpha 1 and alpha 2 adrenergic receptors.

The synthesis and pharmacology of 2-(5,6-dihydroxy-1,2,3,4-tetrahydro-1-naphthyl)imidazoline (A-54741, 4), a very potent alpha-adrenergic agonist, are described. The change in biological activity resulting from variation of the carbocyclic ring size of 4 from four through seven members (2-5) is presented, as well as an explanation that accounts for this change in activity by considering the "exactness of fit" of these compounds to both the alpha 1- and alpha 2-adrenergic receptors. Compound 4 was found in vitro to be a full agonist with greater potency at the alpha 2 receptor (ED50 norepinephrine (NE)/ED50 4 = 188 +/- 22) than at the alpha 1 receptor (ED50 NE/ED50 4 = 13 +/- 2).

Adrenergic and dopaminergic properties of dopamine sulfoconjugates.

UNLABELLED: The 3- and 4-sulfate esters of dopamine (DA-3-SO4 and DA-4-SO4, respectively), the two main metabolites of DA, were evaluated for potential intrinsic or indirect catecholaminergic activities. Both compounds lacked any appreciable affinities for alpha 1, alpha 2, beta 1, beta 2 and DA-2 receptors. In the superfused [3H]norepinephrine-preloaded dog saphenous vein, both dopamine sulfates were devoid of any intrinsic inhibitory activity such as observed with dopamine pre- and postsynaptically. In addition, they did not displace the labeled vesicular neurotransmitter as did dopamine. In anesthetized dogs the two compounds failed to stimulate either the dopaminergic receptors (DA-1) of mesenteric vascular beds or the adrenergic receptors mediating the vasodilatory and pressor responses to dopamine. CONCLUSION: In our experimental conditions DA-3-SO4 and DA-4-SO4, the products of dopamine sulfoconjugation, lacked any demonstrable intrinsic affinity and/or efficacy on the dopaminergic and adrenergic receptors directly or indirectly through their metabolic transformation or through displacement of endogenous neurotransmitter.

Conformationally defined adrenergic agents. 1. Design and synthesis of novel alpha 2 selective adrenergic agents: electrostatic repulsion based conformational prototypes.

A previous report of the adrenergic selectivity of 2- and 6-fluoronorepinephrine prompted us to formulate a hypothesis that accounted for this selectivity on the basis of a conformational preference induced by electrostatic repulsion between the aromatic fluorine atom and the side-chain hydroxyl group. A series of nitrogen-substituted catechol (aminomethyl)benzocyclobutenes, indanes, tetralins, and benzocycloheptenes were prepared, and when their radioligand binding affinities were determined, it was found that the overall pattern of binding affinity results supported the electrostatic repulsion hypothesis. The radioligand binding assay also revealed several highly alpha 2 selective adrenergic agents among these compounds, with the binding selectivity maximizing for compounds having nitrogen substituted with a group no larger than methyl and having a five-membered carbocyclic ring (i.e., 16, 17, and 19).