.alpha.- and .beta.-Adrenoceptors: From the Gene to the Clinic. 2. Structure-Activity Relationships and Therapeutic Applications

Rr, Ruffolo; Bondinell, William E.; Jp, Hieble

doi:10.1021/jm00019a001

Cited by 182 publications

(138 citation statements)

References 95 publications

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“…When neither the control nor the respective 5-HT agonist (8-OH-DPAT or PCA)-treated groups differed from each other with respect to both, training and retention latencies, the results obtained in the combination studies with different doses of the 5-HT antagonists were pooled. Beique et al 1998;Forster et al 1995;Hoffman et al 1991;Hoyer 1989;Hoyer et al 1994;Kennett 1993;Leysen et al 1993;Martin et al 1998;Middlemiss 1986;Ruffolo et al 1995;Schuldiner et al 1993;Wall et al 1995 …”

Section: Discussionmentioning

confidence: 99%

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Multiple 5-HT Receptors in Passive Avoidance Comparative Studies of p-Chloroamphetamine and 8-OH-DPAT

Misane

2000

Neuropsychopharmacology

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KEY WORDS : Passive avoidance; 5-HT receptors; 8-OH-DPAT; p-chloroamphetamine (PCA); m-chlorophenylpiperazine (mCPP); dopamineSerotonergic (5-HT) projections, arising from the midbrain raphe nuclei (Jacobs and Azmitia 1992; Vertes 1991) innervate limbic (amygdala and hippocampus) and cortical areas known to be involved in the cognition and processing of emotional events (Ambrogi Lorenzini et al. 1998;Gallagher and Chiba 1996;Heilman and Gilmore 1998;Lavond et al. 1993;Ledoux and Müller 1997;Pezzone et al. 1992).To investigate the role of the limbic and cortical 5-HT in behavior, different appproaches have been employed ranging from manipulations that result in multiple re- Received December 23, 1998; revised May 18, 1999; accepted July 13, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 2 Multiple 5-HT Receptors in Passive Avoidance 169 ceptor stimulation to the selective activation of 5-HT receptor subtypes. The former approach is of particular importance, because 5-HT neurotransmission seems to operate largely via non-or extrasynaptic mode of communication, also known as volume transmission (Agnati et al. 1995;Bunin and Wightman 1998;Descarries et al. 1990;Descarries et al. 1975;Dewar et al. 1991;Jansson et al. 1998). Thus, released 5-HT can act at a distance at multiple 5-HT receptors far away from the synaptic cleft, whereas selective 5-HT agonists act on all receptors of a specific subtype.Earlier studies have shown that treatments that increase 5-HT activity in the brain, such as 5-HT-releasing compounds [p-chloroamphetamine (PCA), MDMA, and MMAI] (Marona- Lewicka et al. 1996;McNamara et al. 1995;Ögren 1985b;Romano and Harvey 1994;Santucci et al. 1996) as well as the selective 5-HT reuptake inhibitors (SSRIs) (Altman et al. 1984;Lalonde and Vikis-Freibergs 1985;Lucki and Nobler 1985;McElroy et al. 1982;Meneses and Hong 1995;Ögren 1985b) can both enhance and impair performance in aversive learning tasks. Pretraining administration of PCA has been found to produce a marked impairment of both one-and two-way active avoidance acquisition and retention in the rat (Ögren 1982).Although PCA also causes an acute release of dopamine (DA) (Crespi et al. 1997;Henderson et al. 1993;Johnson et al. 1990;Ögren 1985b;Sharp et al. 1986) as well noradrenaline (NA) (Ögren 1982; Ögren 1985a) in the rat brain, its behavioral effects are mediated primarily via serotonergic mechanisms (Adell et al. 1989;Geyer 1996;Hutson and Curzon 1989;Trulson and Jacobs 1976). In support of this, the one-way active avoidance deficit by PCA was completely blocked when the rats were pretreated with 5-HT reuptake inhibitors zimeldine and fluoxetine but not by the NA uptake inhibitor desipramine (Ögren 1982). Zimeldine also blocked the 5-HT release induced by PCA (Ögren et al. 1982). Several nonselective 5-HT 2 antagonists, which, by themselves, did not impair avoidance learning, also produced a dose-dependent blockade of the PCAinduced deficit (Ögren 1986b). This finding suggested that the impairment of active avoidance acquisit...

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Section: Discussionmentioning

confidence: 99%

“…Based on Refs. Beique et al 1998;Forster et al 1995;Hoffman et al 1991;Hoyer 1989;Hoyer et al 1994;Kennett 1993;Leysen et al 1993;Martin et al 1998;Middlemiss 1986;Ruffolo et al 1995;Schuldiner et al 1993;Wall et al 1995).…”

Section: Discussionmentioning

confidence: 99%

Multiple 5-HT Receptors in Passive Avoidance Comparative Studies of p-Chloroamphetamine and 8-OH-DPAT

Misane

2000

Neuropsychopharmacology

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“…15,31 Since high concentrations of antagonists were used in these studies, the selectivity of the antagonists for alpha-1 and alpha-2 adrenergic receptors is compromised at high drug concentrations due to lack of speci®city. 46,51,54 Therefore, the assignment of a speci®c functional activity to a speci®c receptor class or subclass based only on pharmacological analyses is suggestive, at best. Further, although yohimbine and rauwolscine (highly selective alpha-2 adrenergic receptor anta- Figure 4 Proposed molecular mechanism of action of alpha-1 adrenergic receptors in penile corpus cavernosum smooth muscle cells.…”

Section: Classi®cation Of Alpha-adrenergic Receptor Subtypes In Humanmentioning

confidence: 99%

“…Although phentolamine has been used as an intracavernosal and oral agent in treatment of erectile dysfunction (reviewed in refs 27, 67), a detailed analysis of its mechanism of action in erectile tissue was not reported. Several classes of alpha adrenergic blockers have been synthesized and screened for their potential usefulness in inhibiting receptor activity (reviewed in refs 46,51). Different alpha-adrenergic receptor blockers possess various structural determinants that confer selectivity, af®nity and ef®cacy ( Figure 7).…”

Section: Alpha Adrenergic Receptor Blockade In Erectile Dysfunctionmentioning

confidence: 99%

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Role of alpha adrenergic receptors in erectile function

et al. 2000

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Penile erection is a complex physiological process in which the regulation of penile hemodynamics depends on signal input from central and peripheral nervous systems, and on the balance and interplay between several local physiological mediators (neurotransmitters, vasoactive agents and endocrine factors). A role for the sympathetic nervous system in attaining or maintaining penile¯accidity and detumescence is well recognized. However, the exact mechanisms of alpha-adrenergic receptor mediated erectile function remain poorly de®ned. The objective of this review is to summarize data presented in the literature and from our laboratory on alpha-adrenergic receptors, and to discuss the conceptual framework by which the alphaadrenergic receptor pathway modulates penile corpus cavernosum smooth muscle contractility. We will integrate the current state of knowledge of penile erection into one framework encompassing the biochemical and physiological pathways responsible for trabecular smooth muscle relaxation (erection) and contraction (detumescence). We will focus our discussion on local control mechanisms of alpha-adrenergic receptors and explore the following topics: (1) functional activity of alpha-1 and alpha-2 adrenergic receptors in the physiology of human penile erection; (2) identi®cation, classi®cation and characterization of alpha-1 and alpha-2 adrenergic receptor subtypes in human penile erectile tissue; (3) molecular mechanism of action of alpha-1 and alpha-2 adrenergic receptors in human penile erectile tissue; (4) blockade of alpha-1 and alpha-2 adrenergic receptor action by selective and non-selective alpha-1 and alpha-2 adrenergic receptor antagonists (blockers); (5) physiologic (functional) antagonism of alpha-1 and alpha-2 adrenergic receptor activity by vasodilators mediating smooth muscle relaxation; and (6) key areas of consensus, as well as critical gaps in the existing scienti®c knowledge concerning the rationale and the potential use of alpha-blockers in erectile function.

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Molecular mechanics study of transannular amine-ketone (N?C(DOUBLE BOND)O) interaction in medium-sized heterocycles

Griffith¹,

Bremner²,

Titmuss³

1997

J. Comput. Chem.

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.alpha.- and .beta.-Adrenoceptors: From the Gene to the Clinic. 2. Structure-Activity Relationships and Therapeutic Applications

Cited by 182 publications

References 95 publications

Multiple 5-HT Receptors in Passive Avoidance Comparative Studies of p-Chloroamphetamine and 8-OH-DPAT

Multiple 5-HT Receptors in Passive Avoidance Comparative Studies of p-Chloroamphetamine and 8-OH-DPAT

Role of alpha adrenergic receptors in erectile function

Molecular mechanics study of transannular amine-ketone (N?C(DOUBLE BOND)O) interaction in medium-sized heterocycles

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