Adrenoceptor Subtypes

Kaumann, A. J., and Marano, M. (1982). On equilibrium dissociation constants for complexes of drag receptor subtypes Selective and nonselective interactions of partial agonists with two P-adrenoceptor subtypes mediating positive chronotropic effects of (-) isoprenaline in kitten atria. Nannyn Schmiedebeberg s Arch. Pharmacol. 219 216—221. 

Regulation of transmitter release does not rest solely on the frequency at which nerve impulses reach the terminals. Early experiments using stimulated sympathetic nerve/end-organ preparations in situ, or synaptosomes, indicated that release of [ HJnoradrenaline was attenuated by exposure to unlabelled, exogenous transmitter. This action was attributed to presynaptic adrenoceptors, designated a2-adrenoceptors, which were functionally distinct from either aj- or )S-adrenoceptors. Later experiments have confirmed that ai-adrenoceptors comprise a family of pharmacologically and structurally distinct adrenoceptor subtypes. 

Starke, K (1987) Presynaptic a-autoreceptors. Rev. Physiol. Biochem. Pharmacol. 107 73-146. Zhong, H and Minneman, KP (1999) i-Adrenoceptor subtypes Eur. J. Pharmacol. 375 261-276. Zigmond, RE, Schwarzschild, MA and Rittenhouse, AR (1989) Acute regulation of tyrosine hydroxylase by nerve activity and by neurotransmitters via phosphorylation. Ann. Rev. Neurosci. 12 451-461. 

Bremner,. B., Coban, B., Griffith, R Groenewoud, K. M., Yates, B. F. Ligand design for alpha] adrenoceptor subtype selective antagonists. Bioorg. Med. Chem. 2000, 8, 201-214. 

N-methyl-actinodaphnine possesses 5-hydroxytryptamine receptor blocking activity and a selective antagonist of cq-adrenoceptors, selective for the a1B. than for the a1A-adrenoceptor subtype (14). What are the activities of N-methyl-actinodaphnine and other aporphines of Illigera and Hernandia species against topoisomerase ... 

Hancock, A.A. (1996) a 1-Adrenoceptor adrenoceptor subtypes a synopsis of their pharmacology and molecular biology. Drug Development Research, 39, 54-107. 

De Benedetti, P.G., Heible, J.P. and Giardina, D. (1996) al-Adrenoceptors subtype- and organ-selectivity of different agents, in Perspectives in... 

Michel, M.C., Kenny, B. and Schwinn, D. A. (1995) Classification of alpha 1-adrenoceptor subtypes. Naunyn-Schmiedebergs Archives of Pharmacology, 352, 1-10. 

De Benedetti, P.G., Fanelli, F., Menziani, M.C., Cocchi, M., Testa, R. and Leonardi, A. (1997) Alpha 1-adrenoceptor subtype selectivity molecular modelling and theoretical quantitative structure-affinity relationships. Bioorganic el Medicinal Chemistry, 5, 809-816. 

MacDougall, I.J. and Griffith, R. (2006) Selective pharmacophore design for alphal-adrenoceptor subtypes. Journal of Molecular Graphics el Modelling, 25, 146-157. 

Balls, T., Andersen, K., Soby, K.K., and Liljefors, T. al Adrenoceptor subtype selectivity 3D-QSAR models for a new class of al adrenoceptor antagonists derived from the novel antipsychotic sertindole./. Mol. Graph. Mod. 2003, 21, 523-534. 

Knowledge of structure-activity relationships has permitted the synthesis of sympathomimetics that display a high degree of selectivity at adrenoceptor subtypes. 

Arnsten AFT, Leslie FM (1991) Behavioural and receptor binding analysis of the Oj-agonist, UK-14304 (5 bromo-6 (2-imidazoline-2-yl amino) quinoxaline) evidence for cognitive enhancement at an a -adrenoceptor subtype. Neuropharmacology 30 1279-1289... 

Rohrer DK, Kobilka BK (1998) G protein-coupled receptors functional and mechanistic insights through altered gene expression. Physiol Rev 78 35-52 Rosin DL, Talley EM, Lee A, Stornetta RL, Gaylinn BD, Guyenet PG, Lynch KR (1996) Distribution of aj -adrenergic receptor like immunoreactivity in the rat central nervous system. J Comp Neurol 372 135-165 Ruffolo RR, Nichols AJ, Stadel ]M, Hieble JP (1993) Pharmacologic and therapeutic applications of a2-adrenoceptor subtypes. Aim Rev Pharmacol Toxicol 32 243-279... 

Fig. 2. Schematic drawing of the adrenergic neurotransmission. Dependent on the target organ, the postsynaptic, G-protein-coupled receptors are of the a -, 2- or /Sj-adrenoceptor subtype. A presynaptic 2-adrenoceptor acts as an inhibitory autoreceptor. The predominant elimination pathway of the transmitter noradrenaline (NA) is the neuronal re-uptake...

As mentioned above, the receptors which are sensitive to catecholamines are the so-called adrenoceptors. At least five major subtypes are present and of physiological relevance the a - (pharmacologically subdivided in a A, and ofio), 0(2- (pharmacologically subdivided in o 2A, oi2B and af2c) p2 and y03-adrenoceptor subtypes, which all belong to the G-protein coupled receptor superfamily. 

Adrenoceptors are mostly in the close vicinity of the synaptic cleft whereas 02-adrenoceptors appear to be localized in some distance to this structure. A great number of sympathomimetics and sympa-tholytics exist which display different affinities towards the different adrenoceptor subtypes. This is of considerable therapeutic relevance. 

In contrast to the highly specific structural requirement for ligands at the various adrenoceptor subtypes the re-uptake mechanism (into the axon and into the vesicle) are less discriminative. Compounds without hydroxyl moieties at the phenyl ring have no affinity towards the adrenoceptors but serve as a substrate for the re-uptake mechanisms, thereby competing with noradrenaline and as a consequence increasing its concentration in the synaptic cleft. Drugs enhancing the sympathetic tone by this mechanism are called indirect sympathomimetics, for example tyramine, ephedrine, amphetamine. 

Fig. 5. Influence of substituents at the catecholamine molecule the hydroxyl-groups at the phenyl-ring are mendantory for any affinity to all adrenoceptor subtypes. The substituent at the nitrogen in the side chain determines the degree of affinity...

The sympatholyfics of this type interfere with the /3i- and /S2-adrenoceptor subtypes. Via this mechanism the stimulating influence of the sympathetic nervous system on the heart and the metabolism and its inhibiting influence on smooth muscle is blocked. /3-Adrenoceptor blocking agents, or /3-blockers, mostly have a typical isoproterenol-like structure with an isopropylamine or a tertiary butylamine group and a substituted phenoxy moiety bound to the isopropanol backbone. The substituents determine the physicochemical properties of the particular drug and thereby its pharmacokinetic proflle. 

B. Civantos Calzada, A. Aleixandre de Artinano, a-Adrenoceptor subtypes, Pharmacol. Res. 44 (2001) 195-208. 

Goepel, M., L. Dinh, A. Mitchell, R. F. Schafers, H. Rubben, and M. C. Michel. Do saw palmetto extracts block human alpha 1-adrenoceptor subtypes in vivo Prostate 2001 46(3) 226-232. 

Feuerstein, T.J., Huber, B., Vetter, J., Aranda, H., van Velthoven, V., and Limberger, N. (2000) Characeterization of the aj-adrenoceptor subtype, which functions as aj-autoreceptor in human neocortex. / Pharmacol Exp Ther 294 356-362. 

MacDonald, E., Kobilka, B.K., and Scheinin, M. (1997) Gene targeting-homing in on (Xj-adrenoceptor-subtype function. Trends Pharmacol Sci 18 211—219. 

R. Aantaa, A. Marjamaki, M. Scheinin (1995). Molecular pharmacology of alpha 2-adrenoceptor subtypes. Ann. Med. 27 439. 

Since Ahlquist first proposed the existence of two adrenoceptor subtypes, o and 3, in 1948, the number of receptors has considerably expanded and at present nine distinct adrenoceptor subtypes have been identified. There are two subtypes of the o receptor (ol and o2, with subfamiiies of each of these) and three subtypes of the 3 receptor, 31, (32 and 33. The adrenoceptors are G protein-coupied receptors, but second messenger and G protein iinkage differ between the subtypes, ol-Adrenoceptor activation increases phosphoiipase C via a Gq protein, resuiting in an eievation in intraceiiuiar Ca2+-a2- Adrenoceptors are coupied to a Gi protein and... 

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