Cirazoline

Abstract: A significant advance in the field of neurotransmission was made with the discovery of presynaptic release-modulating alpha-adrenoreceptors on noradrenergic nerve terminals. The concept of presynaptic modulation of noradrenaline release developed in parallel with the pharmacological evidence for two subtypes of alpha-adrenoreceptors as defined by a different profile of affinity and relative order of potencies for agonists and for antagonists. The alpha 1-adrenoreceptor is stimulated preferentially by methoxamine and cirazoline and blocked selectively by prazosin or corynanthine. The alpha 2-adrenoreceptor is stimulated preferentially by agonists such as clonidine, TL-99, GHT-933, and UK-14,304, and the responses mediated by these agonists are selectively blocked by the alpha 2-adrenoreceptor antagonist idazoxan. In blood vessels, both the alpha 1- and the alpha 2-adrenoreceptor subtypes are present postsynaptically, where they mediate vasoconstriction, although the alpha 1-adrenoreceptor is the predominant receptor in vascular smooth muscle. Presynaptically on noradrenergic nerve terminals, the stimulation of inhibitory alpha 2-adrenoreceptors reduces the depolarization-evoked release of the transmitter. In most vascular beds, the alpha 1-adrenoreceptor is also the preferentially innervated subtype. In spontaneously hypertensive rats, smooth-muscle alpha 2-adrenoreceptors mediate vasoconstrictor responses to exogenous noradrenaline and to sympathetic nerve stimulation to a greater extent than in the corresponding normotensive Wystar-Kyoto rats, which may point to a pathophysiological role of these alpha 2-adrenoreceptors in hypertension.

Abstract: The alpha-2 adrenoceptor antagonist idazoxan has been shown to also recognize with high affinity nonadrenoceptor sites (I2-imidazoline sites). In contrast, the 2-methoxy derivative of idazoxan, 2-methoxy idazoxan (RX821002), binds almost exclusively to alpha-2 adrenoceptors. The purpose of this study was to assess and extend the pharmacological characterization of I2-imidazoline sites and alpha-2 adrenoceptors in the human and rat brains. Competition studies with several imidazoli(di)ne/guanidine drugs and other nonrelated structures were performed in cortical membranes against [3H]idazoxan (4 nM in the presence of 10(-6) M I-epinephrine to prevent binding to alpha-2 adrenoceptors) or [3H]RX821002 (1 nM). Drugs such as cirazoline, guanoxan, naphazoline, tolazoline, clonidine, bromoxidine (UK 14,304) and phenylbiguanide displaced [3H]idazoxan from two distinct binding sites, which suggested the existence of two affinity states for I2-imidazoline sites that were not modulated by MgCl2 or the nucleotide analog guanylyl-5'-imido-diphosphate. Binding affinities at the low-affinity site (KiL) were consistently more than 2 orders of magnitude lower than binding affinities at the high-affinity site (KiH), and there was a good correlation between KiH and KiL values for a given drug in the human (r = 0.89) and rat (r = 0.92) brains. For 18 to 22 drugs, the Ki values in the human brain correlated well with the corresponding Ki values in the rat brain both for I2-imidazoline sites (r = 0.94) and alpha-2 adrenoceptors (r = 0.97). However, the Ki values for I2-imidazoline sites did not correlate with the Ki values for alpha-2 adrenoceptors in human and rat brains. The order of drug potency for the I2-imidazoline sites was: guanoxan (1.3 nM) approximately cirazoline > idazoxan approximately naphazoline > clonidine > phentolamine > RX821002 > (8aR, 12aS, 13aS)-3-methoxy-12-methanesulfonyl-5,6,8a,9,10,11,12,12a,13,13a- decahydro-8H-isoquino[2,1-g]-naphthyridine (RS 15385-197) (> 10 microM). In contrast, the potencies at the alpha-2 adrenoceptor were: RS 1538-197 (0.3 nM) > RX821002 > clonidine > phentolamine > idazoxan approximately naphazoline > guanoxan approximately cirazoline (307 nM). The results demonstrate that I2-imidazoline sites (labeled by [3H]idazoxan) and alpha-2 adrenoceptors are different pharmacological entities with similar characteristics in the human and rat brains. In both species, I2-imidazoline sites are markedly heterogeneous in nature.

Abstract: Extensive evidence indicates that stress hormone effects on the consolidation of emotionally influenced memory involve noradrenergic activation of the basolateral complex of the amygdala (BLA). The present experiments examined whether corticotropin-releasing factor (CRF) modulates memory consolidation via an interaction with the beta-adrenoceptor-cAMP system in the BLA. In a first experiment, male Sprague Dawley rats received bilateral infusions of the CRF-binding protein ligand inhibitor CRF(6-33) into the BLA either alone or together with the CRF receptor antagonist alpha-helical CRF(9-41) immediately after inhibitory avoidance training. CRF(6-33) induced dose-dependent enhancement of 48 h retention latencies, which was blocked by coadministration of alpha-helical CRF(9-41), suggesting that CRF(6-33) enhances memory consolidation by displacing CRF from its binding protein, thereby increasing "free" endogenous CRF concentrations. In a second experiment, intra-BLA infusions of atenolol (beta-adrenoceptor antagonist) and Rp-cAMPS (cAMP inhibitor), but not prazosin (alpha(1)-adrenoceptor antagonist), blocked CRF(6-33)-induced retention enhancement. In a third experiment, the CRF receptor antagonist alpha-helical CRF(9-41) administered into the BLA immediately after training attenuated the dose-response effects of concurrent intra-BLA infusions of clenbuterol (beta-adrenoceptor agonist). In contrast, alpha-helical CRF(9-41) did not alter retention enhancement induced by posttraining intra-BLA infusions of either cirazoline (alpha(1)-adrenoceptor agonist) or 8-br-cAMP (cAMP analog). These findings suggest that CRF facilitates the memory-modulatory effects of noradrenergic stimulation in the BLA via an interaction with the beta-adrenoceptor-cAMP cascade, at a locus between the membrane-bound beta-adrenoceptor and the intracellular cAMP formation site. Moreover, consistent with evidence that glucocorticoids enhance memory consolidation via a similar interaction with the beta-adrenoceptor-cAMP cascade, a last experiment found that the CRF and glucocorticoid systems within the BLA interact in influencing beta-adrenoceptor-cAMP effects on memory consolidation.