Selectivity profile of the alpha 2-adrenoceptor antagonist efaroxan in relation to plasma glucose and insulin levels in the rat.

The effects of efaroxan (RX 821037A; 2-[2-(2-ethyl-2,3-dihydrobenzofuranyl)]-2-imidazoline HCl) at alpha 1- and alpha 2-adrenoceptors were investigated in isolated tissues, pithed rats and conscious rats. In isolated tissues, efaroxan competitively antagonised the inhibitory effects of p-aminoclonidine in the electrically stimulated (0.1 Hz) rat vas deferens, (pA2 = 8.89) and the contractile effects of phenylephrine on the rat anococcygeus muscle (pA2 = 6.03). Efaroxan had a selectivity ratio (alpha 2/alpha 1) of 724 compared to a value of 182 for idazoxan. In pithed rats, the i.v. doses of efaroxan (mumol/kg) producing 2-fold shifts in dose-response curves for UK-14,304 at prejunctional cardiac alpha 2-adrenoceptors and postjunctional vascular alpha 2-adrenoceptors, and for cirazoline at postjunctional vascular alpha 1-adrenoceptors, were 0.05, 0.13 and 2.96, respectively. In conscious fasted rats, prazosin (5 mg/kg p.o.) increased resting glucose levels and exacerbated the hyperglycaemic effects of UK-14,304 and adrenaline. In contrast, efaroxan (1-5 mg/kg p.o.) had little effect on resting plasma glucose but markedly antagonised the hyperglycaemic actions of UK-14,304 and adrenaline. Efaroxan increased resting plasma insulin levels and markedly potentiated the rise in insulin levels produced by adrenaline; this latter effect was prevented by the co-administration of propranolol. These results demonstrate that efaroxan is a potent and selective alpha 2-adrenoceptor antagonist and provide further support for the involvement of alpha 2-adrenoceptors in glucose homeostasis.

Comparison of the effects of efaroxan and glibenclamide on plasma glucose and insulin levels in rats.

The effect of efaroxan (1 and 5 mg/kg p.o.; a selective alpha 2-adrenoceptor antagonist) was compared to glibenclamide (1 and 5 mg/kg p.o.; a standard sulphonylurea) on basal plasma glucose levels of fed and fasted rats. In addition, the effect of efaroxan (5 mg/kg p.o.) and glibenclamide (2 or 5 mg/kg p.o.), alone and in combination, on the hyperglycaemia and hyperinsulinaemia induced by glucose challenges, were investigated. An intra-arterial (250 mg/kg i.a.) and a subcutaneous (1 g/kg s.c.) glucose challenge were used to stimulate the fast and slow release phases of insulin secretion. Efaroxan increased plasma insulin levels in both conscious fed and fasted rats without greatly affecting plasma glucose levels. Glibenclamide also elevated insulin levels, but was associated with marked hypoglycaemia. Efaroxan and glibenclamide potentiated the slow and fast release of insulin secretion, but glibenclamide had a tendency to produce hypoglycaemia in these test situations, a property not shared by efaroxan. A combination of efaroxan and glibenclamide produced a greater elevation in the slow and fast insulin release phases than either compound alone, but did not enhance the hypoglycaemia seen with glibenclamide alone. These results provide further evidence that pancreatic alpha 2-adrenoceptors are involved in the regulation of insulin secretion.

Selective alpha 2-adrenoceptor blockade does not enhance glucose-evoked insulin release.

An investigation has been made of the effects of the selective alpha 2-adrenoceptor antagonist, idazoxan, on the plasma immunoreactive insulin and glucose responses following a glucose stimulus in conscious euglycaemic rats. UK 14304 (100 micrograms/kg), a selective alpha 2-adrenoceptor agonist, reduced the insulin response and potentiated the hyperglycaemia elicited by an intra-arterial glucose load (0.25 g/kg), thereby confirming previous findings that alpha 2-adrenoceptors can influence pancreatic insulin secretion and glycaemia. The effects of UK 14304 were totally abolished by idazoxan (1.0 mg/kg), indicating that idazoxan, at the dose studied, effectively antagonized alpha 2-adrenoceptor-mediated responses. However, idazoxan (1.0 mg/kg) by itself did not significantly affect the plasma glucose and insulin responses to glucose challenge. The data indicate that selective alpha 2-adrenoceptor blockade per se does not potentiate glucose-evoked insulin secretion.

The role of alpha- and beta-adrenoceptor subtypes in mediating the effects of catecholamines on fasting glucose and insulin concentrations in the rat.

1. The role of alpha- and beta-adrenoceptor subtypes in the regulation of plasma glucose and immunoreactive insulin (IRI) levels has been investigated in normal conscious fasted rats by employing selective agonists and antagonists. 2. Adrenaline (0.2 mg kg-1)-induced hyperglycaemia was abolished by the selective alpha 2-adrenoceptor antagonist idazoxan (1.0 mg kg-1), unaltered by non-selective beta-adrenoceptor blockade (propranolol, 1.0 mg kg-1) and potentiated by the selective alpha 1-adrenoceptor antagonist prazosin (0.3 mg kg-1). Adrenaline increased plasma IRI levels in the presence of idazoxan but not in the presence of either prazosin or propranolol. 3. The selective alpha 2-adrenoceptor agonists UK 14304 (0.1 and 0.3 mg kg-1) and BHT-920 (0.2 and 0.5 mg kg-1) elicited dose-dependent hyperglycaemic responses, but did not alter plasma IRI levels. UK 14304 (0.1 mg kg-1)-evoked hyperglycaemia was blocked by idazoxan but not by prazosin. 4. The selective alpha 1-adrenoceptor agonists methoxamine (0.3 mg kg-1) and phenylephrine (0.3 mg kg-1) failed to modify either plasma glucose or IRI levels. 5. Isoprenaline (0.2 mg kg-1) elicited hyperglycaemic and insulinotropic responses which were attenuated by propranolol (1.0 mg kg-1) and the selective beta 2-adrenoceptor antagonist ICI 118551 (1.0 mg kg-1), but not by the beta 1-selective antagonists atenolol (1.0 mg kg-1) and betaxolol (1.0 mg kg-1). 6. None of the antagonists per se affected basal plasma glucose or IRI concentrations, except prazosin (1.0 mg kg-1). 7. The results indicate that adrenoceptors do not appear to be involved in regulating basal plasma glucose and IRI concentrations in the fasted rat. However, the effects of catecholamines on these parameters are mediated by alpha 2- and beta 2-adrenoceptors, whereas alpha,- or beta l-adrenoceptors do not appear to be involved.

Alpha-adrenoceptors and insulin release from pancreatic islets of normal and diabetic rats.

The role of alpha-adrenoceptors in the regulation of glucose-induced insulin release (GIR) was investigated in islets of normal and neonatally streptozotocin-injected non-insulin-dependent diabetic rats (STZ). In normal islets GIR was suppressed to approximately 50% by 10(-8) M of the alpha 2-adrenergic agonist UK 14304, whereas 10(-9) M of the agonist induced a similar inhibition in STZ islets. In normal islets, suppression of GIR by UK 14304 (10(-8) M) was totally antagonized by 10(6) M idazoxan (alpha 2-antagonist) or 10(6) M phentolamine (alpha 1 + alpha 2-antagonist). In STZ islets, the inhibitory effect of UK 14304 (10(-9) M) was entirely reversed by 10(-5) M idazoxan or 10(-6) M phentolamine. The alpha 1-antagonist prazosin (10(-7)-10(-5) M) was without effect on insulin release suppressed by UK 14304 in normal and STZ islets. Insulin release at 3.3, 8.3, or 16.7 mM glucose was augmented by phentolamine but not by idazoxan. It is concluded that the inhibitory effect of catecholamines on insulin release is mediated by alpha 2-receptors in normal and STZ islets. Phentolamine augments basal and glucose-induced insulin release by a mechanism that does not involve alpha 2-adrenoceptors.

Alpha 2-adrenoceptor blockade does not enhance glucose-induced insulin release in normal subjects or patients with noninsulin-dependent diabetes.

Studies with phentolamine, an alpha-adrenergic antagonist, in normal subjects and diabetic patients have indicated that insulin secretion may be inhibited by tonic alpha-adrenergic stimulation of pancreatic B-cells. We evaluated, with the use of the highly selective alpha 2-adrenoceptor antagonist idazoxan, the role of alpha 2-adrenergic receptors in the regulation of glucose-induced insulin secretion. A glucose infusion test (GIT) was performed after the administration of idazoxan or placebo in normal men (n = 15) and men with noninsulin-dependent diabetes mellitus (n = 6). The normal men were divided into two groups on the basis of high (n = 8) and low (n = 7) insulin responses to prior GITs. The blood glucose and plasma insulin and C-peptide responses to the GIT were similar after idazoxan (40 mg, orally) or placebo treatment in all three groups, although the responses differed among the groups. In the diabetic group iv administration of idazoxan 20 min before the GIT did not alter the insulin response to the GIT. We conclude that alpha 2-adrenergic blockade does not affect glucose-induced insulin secretion in normal men, nor does it improve the impaired first phase of insulin secretion in low insulin responders and noninsulin-dependent diabetes mellitus patients. Phentolamine probably stimulates insulin secretion by a mechanism not involving alpha 2-adrenergic receptors directly.

Antihypertensive thiadiazoles. 1. Synthesis of some 2-aryl-5-hydrazino-1,3,4-thiadiazoles with vasodilator activity.

Some 2-aryl-5-hydrazino-1,3,4-thiadiazoles have been synthesized and screened for antihypertensive activity. In general, compounds with a 2-substituted phenyl ring had higher activity than their 3- or 4-substituted counterparts or those containing heteroaryl groups. The 2-methylphenyl and 2-ethylphenyl derivatives 7 and 18 were the most potent members of the series. Preliminary studies indicated that the hypotensive action of these compounds was due to a direct relaxant effect on vascular smooth muscle.

Antihypertensive thiadiazoles. 2. Vasodilator activity of some 2-aryl-5-guanidino-1,3,4-thiadiazoles.

Some 2-aryl-5-guanidino-(or N-substituted guanidino)-1,3,4-thiadiazoles and closely related analogues were found to lower blood pressure in metacorticoid (DOCA) hypertensive rats. In the unsubstituted guanidines that exhibited low toxicity, optimum activity resulted when the aryl group was a 2-methylphenyl ring (11). Modifications to the guanidine group did not increase antihypertensive activity, but, in the 2-methylphenyl series, the N-n-butyl- and N-(2-methoxyethyl)guanidines (63 and 78) and the related iminoimidazolidine 93 were of comparable activity to that of the unsubstituted guanidine 11. The iminoimidazolidine 93 showed a somewhat longer duration of action than the guanidine derivatives. Preliminary studies in a pithed rat preparation indicated that these thiadiazole derivatives (11, 63, and 93) lowered blood pressure by a direct relaxant effect on vascular smooth muscle.

The use of ex vivo platelet aggregation to confirm the in vivo alpha 2-adrenoreceptor antagonist effect of idazoxan in man.

The aggregation of human platelets induced by adrenaline has been used as a test system to investigate the in vivo effect of the alpha 2-adrenoreceptor antagonist idazoxan during initial intravenous studies with increasing doses. The inhibitory effect of idazoxan in vitro was confirmed; addition of idazoxan to platelet suspensions prior to adrenaline caused a competitive inhibition of the aggregatory response by specific antagonism of the platelet alpha 2-adrenoreceptor. Following intravenous infusions of increasing doses of idazoxan to volunteers, a dose-dependent inhibition of the ex vivo aggregatory response to adrenaline was observed in isolated platelet suspensions compared to predose values. The inhibitory effects of idazoxan in vivo declined in a biphasic manner with a more rapid fall over the first hour. This reflects the kinetics of the drug in plasma and the semilogarithmic nature of the concentration-response line observed in vitro. Intravenous doses of 100 and 300 micrograms/kg were demonstrated to be effective antagonist doses of the platelet alpha 2-adrenoreceptor in healthy volunteers.

Plasma growth hormone in acromegalic patients. Demonstration of highly reproducible diurnal profiles in individual patients.

The effects of the selective alpha 2-adrenoreceptor antagonist idazoxan on diurnal variations in plasma growth hormone levels were studied in acromegalic patients. Seven patients entered the study; six patients had been unsuccessfully treated with either pituitary adenotomy, bromocriptine or other drug therapy or a combination of the two procedures. Plasma growth hormone levels were measured at hourly intervals over a period of 24 h under control conditions and following 4 days treatment with either placebo or idazoxan (20 mg po, three times a day); the comparison of idazoxan with placebo was a double blind cross-over study. Except in one patient, the diurnal growth hormone plasma profiles were virtually superimposable under control conditions and following either placebo or idazoxan; each patient had a characteristic profile. Four patients had impressive nocturnal elevations ranging from about 40 to 200 per cent above average daytime levels. Only one had definite paradoxical early postprandial peaks. These observations are contrary to accepted views on growth hormone levels in acromegalic patients. The majority of our patients thus had profiles reminiscent of the normal diurnal plasma growth hormone pattern albeit at a higher level indicating some preserved central drive. The rather high prevalence in the present study of patients having relapses after adenomectomy may indicate that a selection had been made of cases with hypothalamic aetiology. Administration of the selective alpha 2-adrenoreceptor antagonist idazoxan did not modify plasma growth hormone profiles in these patients.

Alpha-adrenoreceptor reagents. 3. Synthesis of some 2-substituted 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists.

The synthesis and pharmacological activity of a series of 2-substituted derivatives of the selective alpha 2-adrenoreceptor antagonist idazoxan (RX 781094) is described. Substitution in this position by alkyl, alkenyl, cycloalkenyl, and alkoxy groups in many cases gives compounds whose potencies and selectivities are significantly greater than those of the parent compound.

Effects of desipramine on stimulation-induced contractions of the vas deferens of rats pretreated either chronically with desipramine or acutely with idazoxan.

In the present studies the effects of desipramine on the functional sensitivity of the prejunctional alpha 2-adrenoceptors of the vas deferens were studied in pithed rats; contractions of the tissue were evoked by electrical stimulation (6 Hz) of the spinal sympathetic outflow. Twenty-four hours after a single dose of desipramine (10 mg/kg, intraperitoneally) the inhibitory dose-response curves to either UK 14 304 or desipramine itself did not differ significantly from those seen in control animals, whereas both were displaced significantly to the right after 15 days pretreatment with desipramine. Thus the functional responsiveness of the prejunctional alpha 2-adrenoceptors of the vas deferens was reduced by chronic but not acute pretreatment with desipramine. In acute studies desipramine (0.3-4.3 mg/kg, intravenously) inhibited electrically induced contractions of the vas deferens of pithed rats. In the presence of the selective alpha 2-adrenoceptor antagonist idazoxan (1 mg/kg, intravenously) desipramine potentiated nerve stimulation. Although idazoxan (10-1440 micrograms/kg, intravenously) itself potentiated electrically induced contractions of the vas deferens the potentiation observed was markedly less than that obtained in rats pretreated acutely with desipramine (0.3 mg/kg, intravenously). Acute simultaneous blockade of both prejunctional alpha 2-adrenoceptors and uptake into nerve terminals can produce maximal potentiation of the contraction of the vas deferens to sympathetic nerve stimulation. Results are discussed in relation to the hypothesis that the combination of an uptake inhibitor and a prejunctional alpha 2-adrenoceptor antagonist, by enhancing noradrenergic transmission, may provide an antidepressant therapy with rapid onset of action.

Selectivity and potency of 2-alkyl analogues of the alpha 2-adrenoceptor antagonist idazoxan (RX 781094) in peripheral systems.

The profiles of four analogues of idazoxan have been examined at alpha-adrenoceptors and the results compared to those obtained with idazoxan and yohimbine. The compounds possessed either a methyl (RX 801079), ethyl (RX 811033), n-propyl (RX 811054) or isopropenyl (RX 811005) group at the two position of idazoxan. The rank order of antagonist potency against UK-14,304 at prejunctional alpha 2-adrenoceptors of the rat isolated vas deferens was RX 811054 greater than RX 811033 greater than idazoxan greater than RX 811005 greater than yohimbine = RX 801079. All compounds were competitive antagonists. The rank order of antagonist potency against noradrenaline at postjunctional alpha 1-adrenoceptors of the rat isolated anococcygeus muscle was RX 811054 = RX 811033 = idazoxan = yohimbine greater than RX 811005 = RX801079. All compounds were competitive antagonists. The rank order of alpha-adrenoceptor selectivity (alpha 2/alpha 1) was RX 811005 greater than RX 801079 greater than RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine. In pithed rats, intravenous administration of all compounds fully reversed the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. In pithed rats the rank order of antagonist potency against UK-14,304 at cardiac prejunctional alpha 2-adrenoceptors was RX 811054 greater than RX 811033 greater than idazoxan greater than yohimbine greater than RX 811005 greater than RX 801079. In contrast, the rank order of antagonist potency against cirazoline pressor effects (vascular postjunctional alpha 1-adrenoceptors) was RX 811054 greater than RX 811033 greater than yohimbine greater than idazoxan greater than RX 811005 greater than RX 801079. The rank order of alpha 2-adrenoceptor selectivity was RX 811033 = RX 801079 = RX 801005 greater than RX 811054 greater than idazoxan greater than yohimbine. Although idazoxan produced contractions of the anococcygeus muscle and increased blood pressure in pithed rats, three of the analogues (RX 811005, RX 801079 and RX 811033) were inactive. In conclusion, alkyl substitution in the 2-position of idazoxan can enhance either alpha 2-adrenoceptor antagonist potency or selectivity or both and furthermore, the weak partial alpha 1-adrenoceptor agonist properties of idazoxan can be removed.

Alpha-adrenoreceptor reagents. 2. Effects of modification of the 1,4-benzodioxan ring system on alpha-adrenoreceptor activity.

Modification of the 1,4-benzodioxan ring present in RX 781094 has not previously been considered. This paper describes a number of analogues of this ring system, including compounds in which one of the oxygen atoms has been replaced by a methylene group and also those in which the ring size has been changed to give, for example, furan and thiophene derivatives. The dihydrobenzofuranylimidazoline compound 7 is the only analogue possessing presynaptic antagonist potency potency and selectivity comparable to that of 1. In view of this result, a number of derivatives was prepared to determine the structure-activity relationships within this series. Many derivatives, as well as the parent compound 7, were found to possess presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties. Two of the selective presynaptic antagonists, 13 and 14 possess greater potency and selectivity than that possessed by 1. The 5-chloro derivative 25 is twice as potent as after oral administration but only about half as potent when given intravenously.

Comparison of the alpha-adrenoceptor antagonist profiles of idazoxan (RX 781094), yohimbine, rauwolscine and corynanthine.

In the present studies the potency and selectivity of idazoxan (RX 781094) were compared with yohimbine and its diastereoisomers rauwolscine and corynanthine in both functional studies and radioligand binding experiments. Prejunctional alpha 2- and postjunctional alpha 1-adrenoceptor antagonist potencies were assessed by determining pA2 values against clonidine on the stimulated rat was deferens and noradrenaline on the anococcygeus muscle, respectively. The rank order of prejunctional alpha 2-adrenoceptor antagonist potency was idazoxan greater than yohimbine greater than rauwolscine much greater than corynanthine. At postjunctional alpha 1-adrenoceptors the rank order of antagonist potency was rauwolscine greater than corynanthine greater than yohimbine greater than idazoxan. The selectivity values (alpha 2/alpha 1) for idazoxan, yohimbine, rauwolscine and corynanthine were 245, 45, 3 and 0.03 respectively. The selectivity and potency profiles established for these antagonists in functional studies were confirmed in radioligand binding studies utilising 3H-idazoxan (alpha 2) and 3H-prazosin (alpha 1) in rat cerebral cortex. In pithed rats intravenously administered idazoxan, yohimbine and rauwolscine fully reversed the inhibitory effects of clonidine on electrically-induced contractions of the vas deferens; idazoxan was approximately ten times more potent than both yohimbine and rauwolscine. Corynanthine was inactive. Idazoxan and yohimbine also fully antagonised the inhibitory effects of guanabenz on electrically-induced contractions of the anococcygeus muscle; idazoxan again was more than ten times more potent than yohimbine in this model. The inhibitory effects of guanabenz were less readily antagonised by rauwolscine indicating that the selectivity of this compound is less than that of yohimbine in this tissue. Corynanthine was again inactive.(ABSTRACT TRUNCATED AT 250 WORDS)

Sleeping times evoked by alpha adrenoceptor agonists in two-day-old chicks: an experimental model to evaluate full and partial agonists at central alpha-2 adrenoceptors.

The ability of a series of alpha adrenoceptor agonists to induce a sleep-like state (as measured by the time interval between the loss and regaining of the righting reflex) has been assessed in 2-day-old chicks in order to understand their pharmacological profile better. Guanabenz, guanoxabenz, UK-14,304, guanfacine and xylazine produced dose-related increases in sleeping time, the highest dose of these agonists causing the chicks to sleep for over 120 min. In contrast, the dose-response curves to tiamenidine and clonidine were flatter and bell-shaped with maxima of 30 and 60 min, respectively. The effects of all these compounds were antagonized by idazoxan (RX781094) and yohimbine (two selective alpha-2 adrenoceptor antagonists) but were moderately enhanced or unaffected by prazosin (a selective alpha-1 adrenoceptor antagonist) confirming that the state of arousal in chicks can be depressed by stimulation of alpha-2 adrenoceptors. In particular, idazoxan displaced significantly the guanoxabenz dose-response curve to the right without affecting its slope and apparent maximum and blocked the sleep induced by clonidine. However, idazoxan failed to affect the sleep evoked by ethanol, etorphine or pentobarbital. Naloxone antagonized the effects of etorphine but not those of guanoxabenz, ethanol or pentobarbital. The relatively selective alpha-1 adrenoceptor agonist, cirazoline, given in doses up to 20 mg/kg i.m., produced in chicks behavioral manifestations suggestive of enhanced arousal.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for pharmacological similarity between alpha 2-adrenoceptors in the vas deferens and central nervous system of the rat.

Seven alpha 2-adrenoceptor antagonists with diverse chemical structures have been examined for their effects at alpha 2-adrenoceptors in the vas deferens and central nervous system of the rat. Antagonist potency assessed against the presynaptic alpha 2-adrenoceptor agonist action of clonidine in the isolated vas deferens (RX 781094 greater than Wy 26703 greater than yohimbine greater than rauwolscine greater than piperoxan greater than mianserin greater than RS 21361) was highly correlated with the ability of these drugs to displace saturable [3H]-RX 781094 binding from cerebral cortex membranes. Similarly, antagonist potency in the vas deferens was highly correlated with antagonist activity in reversing the centrally-mediated mydriasis induced by the selective alpha 2-adrenoceptor agonist, guanoxabenz, in pentobarbitone-anaesthetized rats. The results indicate that the presynaptic alpha 2-adrenoceptors in the vas deferens are pharmacologically similar to characterized these alpha 2-adrenoceptors in the central nervous system of the rat.

Comparison of the alpha-adrenoceptor profiles of clonidine and two oxygenated arylamino imidazolines.

The profiles of 2-(3,4-dimethoxyphenylamino)-imidazoline HCl (RX 77171) and 2-[6-(1,4-benzodioxanylamino)]imidazoline maleate (RX 801074) were compared with that of clonidine in isolated tissues and pithed rats. RX 77171 consistently displayed prejunctional alpha 2-adrenoceptor antagonist and postjunctional agonist properties. In contrast, RX 801074 had a complex profile which showed considerable variability between tissues. This variability is highlighted by comparing its effects at the prejunctional alpha 2-adrenoceptors of the isolated vas deferens and guinea-pig ileum; in the former RX 801074 was an agonist whereas only antagonist properties were apparent in the ileum.

alpha-adrenoreceptor reagents. 1. Synthesis of some 1,4-benzodioxans as selective presynaptic alpha 2-adrenoreceptor antagonists and potential antidepressants.

The rational design of RX 781094, 2-(1,4-benzodioxan-2-yl)-2-imidazoline hydrochloride (5), a new potent and selective antagonist of alpha 2-adrenoreceptors, is discussed. A compound that acts as an antagonist at presynaptic alpha 2-adrenoreceptors could be an effective and novel treatment of depression because of its ability to increase the concentration of norepinephrine at central receptor sites. The effects of substituents in the aromatic and imidazoline rings have been examined, as well as the replacement of the imidazoline ring by an amidine function or by other heterocyclic ring systems. None of these derivatives are as potent or selective as 5, although some do display a degree of selectivity as antagonists. Some derivatives were found to possess agonist properties that, with the exception of 23, favored the postsynaptic site. Compounds 9, 12, 16, 21, 30, and 51 possessing presynaptic alpha 2-adrenoreceptor antagonist and postsynaptic alpha 1-adrenoreceptor partial agonist properties were also obtained, and these derivatives could be considered as potential antimigraine agents.

Studies on RX 781094: a selective, potent and specific antagonist of alpha 2-adrenoceptors.

1 The selectivity and specificity of RX 781094 [2-(2-(1,4 benzodioxanyl))2-imidazoline HCl] for alpha-adrenoceptors have been examined in peripheral tissues. 2 In isolated tissue experiments RX 781094 was a competitive antagonist at prejunctional alpha 2-adrenoceptors situated on the sympathetic nerve terminals of the rat (pA2 = 8.56) and mouse (pA2 = 7.93) vas deferens and on the parasympathetic nerve terminals of the guinea-pig ileum (pA2 = 8.55). 3 Although RX 781094 was also a competitive antagonist at the postjunctional alpha 1-adrenoceptors of the rat anococcygeus muscle (pA2 = 6.10) its affinity for these receptors was markedly less than that displayed for prejunctional sites. From pA2 values obtained in the rat vas deferens and anococcygeus muscle the calculated alpha 2/alpha 1-adrenoceptor selectivity ratio for RX 781094 was 288. 4 The rank order of alpha 2/alpha 1-adrenoceptor selectivities for the antagonists studied was RX 781094 greater than RS 21361 greater than yohimbine greater than piperoxan greater than phentolamine greater than WB 4101 greater than prazosin. 5 RX 781094 had extremely low affinity for beta-adrenoceptors, histamine receptors, cholinoceptors, 5-hydroxytryptamine and opiate receptors in vitro. 6 In pithed rats, intravenous administration of RX 781094 antagonized the prejunctional alpha 2-adrenoceptor agonist effects of clonidine and guanabenz on electrically-induced contractions of the vas deferens and anococcygeus muscle respectively. 7 In the vas deferens the rank order of alpha 2-adrenoceptor antagonist potencies was RX 781094 greater than phentolamine greater than piperoxan greater than yohimbine greater than RS 21361 greater than WB 4101. Only RX 781094, yohimbine and RS 21361 were active against guanabenz in the anococcygeus muscle. 8 In the pithed rat, RX 781094 preferentially antagonized the pressor responses evoked by postjunctional alpha 2-adrenoceptor activation by UK 14,304 although higher doses also inhibited the effects of phenylephrine and cirazoline at postjunctional alpha 1-adrenoceptors. 9 RX 781094 had little effect on the cardiovascular responses to 5-hydroxytryptramine, angiotensin II, histamine, acetylcholine and isoprenaline in pithed rats and rats anaesthetized with pentobarbitone. 10 These results demonstrate that RX 781094 is a potent and selective alpha 2-adrenoceptor antagonist with a high degree of specificity for these receptors.