It is concluded that α2-adrenoceptors may be promising targets in the antipsychotic therapy.

Dopaminergic, serotonergic, and adrenergic receptors are targets for therapeutic actions in schizophrenia. Dopamine D 2 receptor partial agonists such as aripiprazole represent a treatment option for patients with this severe disorder. The ineffectiveness of terguride, another D 2 receptor partial agonist, in treating schizophrenia was recently attributed to its considerably high intrinsic activity at D 2 receptors. In this study, we used functional assays for recombinant D 2 receptors and native 5-hydroxytryptamine 2A (5-HT 2A ), a 2C -adrenergic, and histamine H 1 receptors to compare the pharmacological properties of terguride and three of its halogenated derivatives (2-chloro-, 2-bromo-, 2-iodoterguride) with those of aripiprazole. Subsequently, we studied the antidopaminergic effects of 2-bromoterguride using amphetamine-induced locomotion (AIL (hD 2S ) receptors that were half as high as the intrinsic activity for terguride; aripiprazole lacked agonist activity. 2-Bromoterguride and aripiprazole activated D 2S receptor-mediated inhibition of cAMP accumulation to the same extent; intrinsic activity was half as high as that of terguride. All compounds tested behaved as antagonists at human D 2long /Ga o (hD 2L /Ga o ) receptors. Compared with aripiprazole, terguride and its derivatives displayed higher affinity at porcine 5-HT 2A receptors and a 2C -adrenoceptors and lower affinity at H 1 receptors. 2-Bromoterguride inhibited AIL and did not induce catalepsy in rats. Because of its in vitro and in vivo properties, 2-bromoterguride may be a strong candidate for the treatment of schizophrenia with a lower risk to induce EPS.

The isolated rat tail artery (RTA) represents an in vitro model of the cutaneous circulation. We have characterised the postjunctional α(2)-adrenoceptor subtype mediating vasoconstriction to the α(2)-adrenoceptor (α(2)-AR) agonist UK14304 in RTA. In non-precontracted arterial rings at 32°C, a physiological temperature for the RTA, UK14304 elicited only slight contractions which were markedly enhanced after precontraction with serotonin (5-HT; 10-50 nM). Under the condition of elevated vascular tone, the contractile UK14304 response was competitively antagonised by MK912 (pA(2) = 10.05 ± 0.07), rauwolscine (pA(2) = 8.82 ± 0.06), yohimbine (pA(2) = 8.45 ± 0.04), WB4101 (pA(2) = 8.05 ± 0.05), BRL44408 (pA(2) = 7.20 ± 0.04), ARC239 (pA(2) = 6.90 ± 0.05) and prazosin (pA(2) = 6.80 ± 0.05). Schild regressions were linear and had slopes of unity. Affinities (pA(2)) for MK912, rauwolscine, yohimbine and WB41104 were in the same range as binding data (pK(D)) for these drugs at α(2C)-ARs of rat cerebral cortex. In addition, the presence of α(2C)-ARs was confirmed by Western blotting. In experiments to study the influence of temperature on vasoreactivity, UK14304-induced contractions did not differ at 37°C, 32°C or 27°C and were similarly blocked by rauwolscine (apparent pA(2) = 8.73-8.90). After rapid cooling (from 37°C to 27°C), the maximal UK14304 response was enhanced only in precontracted arteries; antagonism by rauwolscine was the same before and after cooling (apparent pA(2) = 8.80-8.90). The enhancement of the maximal UK14304 response was abolished by rewarming to 37°C. It is concluded that α(2C)-ARs predominantly mediated vasoconstriction in RTAs at any temperature tested. Since α(2C)-ARs may be involved in Raynaud's phenomenon, the isolated RTA represents a convenient in vitro bioassay to test novel compounds for the treatment of this syndrome.

Enhanced pulmonary vasoconstriction in response to injuries of the central nervous system and hypoxia result in pulmonary edema due to increased sympathetic activation. This study aimed to characterize α(2)-adrenoceptor (AR)-mediated responses in porcine pulmonary arteries. α(2)-AR-mediated vasoconstriction was studied using a tissue bath protocol. α(2)-AR protein was determined by Western blotting. UK14304 (α(2)-AR agonist) elicited only a slight contraction in pulmonary arteries compared to veins. Verapamil (voltage-operated Ca(2+) channel blocker), 2-APB (store-operated Ca(2+) channel inhibitor), and P1075 (K(ATP) channel opener) induced a marked decrease of the basal tone in veins, but not in arteries. The UK14304-induced contraction in arteries was enhanced by (S)-(-)-Bay K 8644 (L-type Ca(2+) channel activator), N (ω)-nitro-L: -arginine methyl ester hydrochloride (L-NAME, eNOS inhibitor), and (S)-(-)-Bay K 8644 plus L-NAME to the same extent. Endothelium denudation failed to affect the UK14304 response. (S)-(-)-Bay K 8644 did not increase the maximal noradrenaline (non-selective α-AR agonist) or phenylephrine (α(1)-AR agonist) response. The rightward shift of the concentration-response curve to noradrenaline by prazosin (α(1)-AR antagonist) plus (S)-(-)-Bay K 8644 was smaller and non-parallel compared to that in the presence of prazosin alone. UK14304 responses were inhibited by MK912 (α(2C)-AR antagonist). Affinity of MK912 (pA(2) 9.76) and Western blotting analysis argue for an involvement of α(2C)-ARs in noradrenaline-induced contraction of pulmonary arteries. It is concluded that postjunctional α(2C)-ARs predominantly mediate contraction in porcine pulmonary arteries when the cytosolic Ca(2+) concentration is elevated. α(2C)-AR antagonists may be beneficial in the treatment of pulmonary edema.

Serotonin (5-hydroxytryptamine; 5-HT) is involved in heart valve tissue fibrosis, pulmonary arterial fibrosis, and pulmonary hypertension. We aimed at characterizing the antiserotonergic properties of the ergot alkaloid derivative terguride [1,1-diethyl-3-(6-methyl-8␣-ergolinyl)urea] by using functional receptor assays and valvular interstitial cell culture. Terguride showed no vasoconstrictor effect in porcine coronary arteries (5-HT 2A receptor bioassay) and no relaxant effect in porcine pulmonary arteries (5-HT 2B receptor bioassay). Terguride behaved as a potent antagonist at 5-HT 2A receptors (noncompetitive antagonist parameter pDЈ 2 9.43) and 5-HT 2B receptors (apparent pA 2 8.87). Metabolites of terguride (NЉ-monodeethylterguride and 6-norterguride) lacked agonism at both sites. NЉ-monodeethylterguride and 6-norterguride were surmountable antagonists at 5-HT 2A receptors (pA 2 7.82 and 7.85, respectively) and 5-HT 2B receptors (pA 2 7.30 and 7.11, respectively). Kinetic studies on the effects of terguride in pulmonary arteries showed that the rate to reach drug-receptor equilibrium for terguride was fast. Washout experiments showed that terguride easily disappeared from the receptor biophase. Pretreatment with terguride inhibited 5-HT-induced amplification of ADP-stimulated human platelet aggregation (IC 50 16 nM). In porcine valvular interstitial cells, 5-HT-induced activation of extracellular signal-regulated kinase (ERK) 1/2, an initiator of cellular proliferation and activity, was blocked by terguride as shown by Western blotting. In these cells, the stimulatory effect of 5-HT on [3 H]proline incorporation (index of extracellular matrix collagen) was blocked by terguride. Because of the inhibition of both 5-HT 2A and 5-HT 2B receptors, platelet aggregation, and cellular proliferation and activity (ERK1/2 phosphorylation and collagen production) terguride may have therapeutic potential in the treatment of fibrotic disorders.

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