Affinity of Serotonin Receptor Antagonists and Agonists to Recombinant and Native α1-Adrenoceptor Subtypes

Abstract

ABSTRACT-Binding affinities of serotonin (5-HT)-receptor antagonists and agonists at human recombinant a1-adrenoceptor subtypes (a 1a-, a1b-and a1d-subtypes) were examined and compared with the functional affinities obtained in rat caudal artery (a1A-subtype), dog carotid artery (a1B-subtype) and rat thoracic aorta (=1D-subtype). Most of the 5-HT-receptor antagonists and agonists tested showed relatively high affinity to three a 1-adrenoceptor subtypes. The highest affinity close to 1 nM was seen for in binding and functional studies. 5-Methylurapidil (5-HT1A agonist) and BMY7378 (5-HT1A agonist) showed, respectively, a 1a(a 1A)-or a1d(a1D)-subtype selectivity in both binding and functional affinities, but spiperone (5-HT2A antagonist) showed a1b-selectivity only in binding affinity. Functional affinity of ritanserin (5-HT2A antagonist) to the a1B-subtype was approximately 500-fold lower than that of affinity to the =1b-subtype. The present results show that many 5-HT-receptor antagonists and agonists have high affinity to a1-adrenoceptors, but suggest that there is deviation between their functional affinities and binding affinities for some drugs.Keywords: Serotonin receptor antagonist, Serotonin receptor agonist, a 1-Adrenoceptor, Selectivity a1-Adrenoceptors comprise a heterogeneous family (1 -3). Molecular biological studies have provided evidence for the existence of at least three genes encoding a1a-, a1b-and a1d-adrenoceptors (with lowercase letters) that correspond to the pharmacologically defined native a1A-, a1B-and a 1D-adrenoceptors (with uppercase letters) (4, 5). Pharmacological studies have revealed several subtypeselective agents: for example, 5-methylurapidil, KMD-3213, RS-17053 and nigludipine for the a1a-subtype (6 -9); spiperone for the a1b-subtype (10); and BMY7378 for the a1d-subtype (11, 12). Among them, 5-methylurapidil, spiperone and BMY7378 were originally categorized in serotonin (5-HT) receptor agonists and / or antagonists.Many 5-HT receptor antagonists have been developed and some of them are now clinically used as anticoagulants, antihypertensive drugs and antipsychotic drugs (13,14). Such therapeutic diversity of 5-HT antagonists may be related to their wide spectrum for not only 5-HT receptor family but also for heterogeneous receptors such as dopamine receptors and a1-adrenoceptors (15, 16).The present study was undertaken to examine the possible selectivity for a1-adrenoceptor subtypes of 5-HT receptor agonists and antagonists including clinically active antipsychotic drugs. The selectivity was evaluated with two parameters: binding affinity to recombinant human a 1a-, a1b-and a1d-adrenoceptors expressed in Chinese hamster ovary (CHO) cells and functional affinity to native a1A-(rat caudal artery) (17), a 1B-(dog carotid artery) (18,19) and a 1D-(rat thoracic aorta) (20) adrenoceptors. A good relationship was already reported for a 1-adrenoceptorselective drugs between the recombinant and native a1-adrenoceptors (7, 21). MATERIALS AND METHODS Membrane preparation and radiolig...

Metachlorophenylpiperazine (m-CPP) induced intracavernous pressure responses in anaesthetized rats

“…9 On the other hand, the same authors demonstrated that the selective a 1a ADR antagonist REC 15=2841 failed to inhibit CN mediated ICP responses in rats or dogs at doses 10 -30 times higher than the dose of spiperone used in the present study. Although we are not able to completely rule out an a-ADR antagonist action for the effect of spiperone on m-CPP induced ICP in the present study, it is interesting to note that ketanserin is comparable to spiperone in terms of affinity and potency as an a 1 -ADR antagonist 23,25 but failed to significantly reduce the m-CPP induced ICP response. Naloxone, yohimbine and 8-OHDPAT have differential effects on erection elicited in different experimental models and were employed here in order to gain some insight into the relevance of the m-CPP induced ICP response to other models of erection.…”

“…10 Spiperone exhibits selectivity for the a 1a ADR subtype. 22,23 Prazosin, a non-selective a 1 -2 antagonist, is often m-CPP induced intracavernous pressure responses ES Hayes and PG Adaikan used to induce erection or enhance erection produced by other agents. 24 However, in anesthetized rats and dogs prazosin tends to reduce ICP elicited by stimulation of the CN but this effect is not clearly dose-dependent and, differs between species.…”

Adrenergic Receptors Modulate Motoneuron Excitability, Sensory Synaptic Transmission and Muscle Spasms After Chronic Spinal Cord Injury

“…In light of the present results and considering that these drugs bind to both adrenergic and serotonergic receptors (Yoshio et al 2001), it now seems likely that these serotonergic drugs also block constitutive activity at ␣ 1 receptors. Constitutively active 5-HT 2 receptors and ␣ 1 adrenergic receptors likely play an equally important role in facilitating spasms, because they contribute equally to PICs and blocking both these receptors essentially eliminates the PICs (Harvey et al 2006b).…”

α1-Adrenergic Receptors Positively Regulate Toll-Like Receptor Cytokine Production from Human Monocytes and Macrophages

“…A similar two-site, high-and low-affinity profile of BMY 7378 was calculated for specific 125 I-HEAT binding sites on these same cells, which confirms mature expression of the ␣ 1D -AR and validates our ␣ 1A -AR subtype observation using 5-MU. Although ␣ 1B -AR expression could be represented as part of the low-affinity binding population for both 5-MU and BMY 7378, previous reports have shown consistent 3-to 4-fold lower binding affinities of BMY 7378 for both recombinant and endogenously expressed ␣ 1A -AR subtypes compared with the ␣ 1B -AR (Yoshio et al, 2001). The extremely low-affinity population (K iL ) identified by BMY 7378 in our human macrophage system correlates well with the calculated BMY 7378 value for ␣ 1A -AR subtypes in the previous report (Yoshio et al, 2001).…”