Adrenoreceptors subtypes

The three P-adrenoreceptor subtypes have varying localizations and functional properties. The brain contains both Pj and Pj receptors the density of Pj receptors varies in different brain areas to a much greater extent than does that of Pj receptors. Pj receptors predominate in the cerebral cortex Pj receptors are more common in the cerebellum. Likewise, there is a coexistence of Pj and Pj receptors in the heart, with both receptor subtypes being coupled to the electrophysiological effects of catecholamines upon the myocardium. Pj receptors tend to predominate in the lung. 

The pharmacologic effects of direct agonists depend on the route of administration, their relative affinity for adrenoreceptor subtypes, and the relative expression of these receptor subtypes in target tissues. The pharmacologic effects of indirect sympathomimetics are greater under conditions of increased sympathetic activity and norepinephrine storage and release. 

Pharmacological studies showed that sila-substitution materials retained significant affinity to human 2 adrenoreceptor subtypes 2a, tXiB and 2c but by one order of magnitude lower than that for the parent 28. 

The advent of molecular biological techniques has made possible to identify and chemically characterize many receptor systems. It has been demonstrated that a high percentage of homology exists not only within receptor subtypes but also among different receptor families. For example, a comparison of the transmembrane domains of G-protein-coupled receptors reveals that muscarinic receptor subtypes have more than 70% identity, whereas a-adrenoreceptor subtypes show a lower identity (about 40%). However, a-adrenoreceptor subtypes share about 45% identity with serotoninergic and dopaminergic receptors [1]. 

Prazosin is a selective competitive ai-adrenoreceptor antagonist widely used not only as a pharmacological tool for ai-adrenoreceptor subtypes characterization but also as an effective agent in the management of hypertension. Its antihypertensive activity depends on a peripheral vasodilatation mediated by a postjunctional aj-adrenoreceptor blockade. Moreover, given its high O]-selectivity, prazosin lacks side effects such as... 

Antagonist affinities of tetraamine disulfides at ai- and a2 adrenoreceptors in the isolated rat vas deferens, and for inhibiting pH]prazosin binding at ai-adrenoreceptor subtypes of rat submaxillary gland (oia) and liver (oib)... 

Affinity constants, expressed as K values, for hybrid tetraamines and reference compounds at aiA- and aiB-adrenoreceptor subtypes are shown in Table 1. These data indicate that, with the exception of 8, hybrid tetraamines... 

In recent years, much effort has been directed towards characterization of receptor systems, which are composed usually of multiple subtypes, a,-Adrenoreceptors do not represent an exception to the rule as they can be divided into at least three subtypes, namely 0, (otuX ib and a,p (a,d), with upper and lower case subscripts being used to designate native or recombinant receptor, respectively (Bylund et al., 1994 Faure et al., 1994 Ford et al., 1994 Hieble et al., 1995). However, some functional experiments indicate that an additional a,-adrenoreceptor subtype may exist, which was named a, L-adrenoreceptor (Docherty, 1998). Efforts to clone this receptor subtype have been unsuccessful so far (Testa et al., 1997), supporting the conclusion that it may represent a different affinity state of the a -adrenoreceptor (Ford et al., 1997 Hieble and Ruffolo, 1997). 

A vast array of structurally unrelated compounds interacts with a I-adrenoreceptor subtypes, which makes it inherently difficult to determine the structural requirements leading to receptor subtypes selectivity (Ruffolo et al., 1995 Leonard et al., 1996 Kenny et al., 1997). The majority of a,-adrenoreceptor antagonists displays a competitive mechanism of action and belongs to a variety of different structural classes such as yohimbanes, ergot alkaloids, quinazolines, A-arylpiperazines, imidazolines, phenylalkylamines, benzodioxanes, indoles, 1,4-dihydro-pyridines, hetero-fused 3-benzazepines, dibenzoquino-lizines. 

Replacing the hexane chain of 2 by a cystamine moiety (Fig. 1) afforded cystazosin (3) which displayed an interesting selectivity profile in comparison with both (-F)-cyclazosin and the carbon analogue 2, owing to a significantly lower affinity for and a,g-adrenoreceptor subtypes relative to the a,D-subtype (vide infra) (Minarini et al., 1998). 

Affinity estimates, expressed as pA",, of the enantiomers of cyclazosin for native and cloned a,-adrenoreceptor subtypes, native a 2-adrenoreceptors, and 5-HT a, and Djreceptors in comparison to prazosin and reference compound spiperone ... 

Fig. 2. Affinity estimates (pM,) of racemic cyclazosin and its enantiomers for cloned a -adrenoreceptor subtypes (oi bovine brain On, hamster smooth muscle 0, rat brain) in comparison to prazosin.

The insertion of a substituent on the benzene ring of 8, affording 9-20, affected differently, according to substituent type and position, the affinity and, as a consequence, the selectivity for a,-adrenoreceptor subtypes (Table 2). 

A most intriguing finding was the observation that polyamines 11, 16 and 20 retained high affinity for a,-adrenoreceptor subtypes which suggests clearly that a 1,6-diaminohexane chain on the benzene ring did not give rise to negative interactions with the receptor. This observation may have relevance for the development of new quinazo-... 

Fig. 4. Affinity constants (pAj) in rat prostatic vas deferens (0, ). spleen (

Affinity constants (p/i ) of 2, 3 and 14 (see Table 2 for structures) for cloned a,-adrenoreceptor subtypes and 5-HT,a receptors in comparison with reference compounds ... 

Membranes were from CHO cells expressing human cloned a,-adrenoreceptor subtypes and HeLa cells expressing human 5-HT, receptors. 

Thus, the affinity for the three a,-adrenoreceptors was not determined, which prevents to draw relevant conclusion on the structural features that determine selectivity for one a,-adrenoreceptor subtype relative to the others. Mephendioxan, a p-tolyl analogue of phendioxan, represents an exception as its enantiomers were assayed at the three cloned a,-adrenoreceptor subtypes. It turned out that, in binding experiment, (-)-25,35-mephendioxan is a selective antagonist for a ( -adrenoreceptors (Quaglia et al., 1996). 

Since it was demonstrated that the other stereoisomers of 30, having a different relationship among the substituents on the cyclopentane unit, were at the best less potent at a,-adrenoreceptors (McCarthy et al., 1985), it was decided to keep constant in hybrid structure I and related compounds the same spatial arrangement as in 30 to possibly achieve the best fit with a,-adrenoreceptor subtypes. Considering the fact that the enantiomers of 21 have different affinity for a,-adrenoreceptors (Nelson et al., 1979 Andrisano et al., 1992), it was of interest to... 

Affinity constants, expressed as p/fj (-log K, nM), of compounds 21, the enantiomers of 31 and 32, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and BMY-7378 for human recombinant a,-adrenoreceptor subtypes and receptors ... 

HT[ receptors. The trend noted above might help in developing relevant structure-activity relationships to differentiate and to understand the structural elements which confer selective interaction at a [-adrenoreceptor subtypes and at 5-HTj receptor. 

Andrisano, V., Marucci, G., Melchiorre, C Tumiatti, V., 1992. Stereoselectivity at a-adrenoreceptor subtypes observations with the enantiomers of WB 4101 separated through their amides of M-tosyl-(S)-proline. Chirality 4, 16-20. 

Role of the ethylene chain separating amine and phenoxy units on the affinity for aj-adrenoreceptor subtypes and 5-HT receptors. J. Med. Chem. 42, 4214-4224. 

Bolognesi, M.L., Budriesi. R., Chiarini, A., Poggesi, E., Leonard , A., Melchiorre, C., 1998. Design, synthesis, and biological activity of prazosin-related antagonists. Role of the piperazine and furan units of prazosin on the selectivity for a,-adrenoreceptor subtypes. J. Med. Chem. 41, 4844-4853. 

Lepretre, N., Mironneau, J., and Morel, J.L. (1994b) Both i a- and 2A-adrenoreceptor subtypes stimulate voltage-operated L-type calcium channels in rat portal vein myocytes. Evidence for two distinct transduction pathways. Journal of Biological Chemistry, 269 29546-29552. 

The generalization made in the past about synaptic locations of adrenoreceptor subtypes was that all ai-. Pi-. inke timulatiot f biochemica rocesse t he ostsynapti c ... 

Carstairs JR, Nimmo AJ, Bames PJ. Autoradiographic visualization of beta-adrenoreceptor subtypes in human lung. Am Rev Respir Dis 1985 132 541-547. 

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