Sven Jähnichen

Fibrotic valvular heart disease is not related to chemical class but to biological function: 5-HT2B receptor activation plays crucial role

Companion letters have been published in this issue of Movement Disorders: Chaudhuri et al., pp 1522–1523, and Rascol et al., pp 1524–1525.

Evidence for 5-HT2B and 5-HT7 receptor-mediated relaxation in pulmonary arteries of weaned pigs

This study characterizes the relaxant response to 5-hydroxytryptamine (5-HT) in prostaglandin F2α (PGF2α)-precontracted pulmonary arteries of weaned pigs. In arterial rings with intact endothelium, the relaxation to 5-HT was biphasic. The high affinity component of relaxation to 5-HT (0.1–10 nM) was abolished by mechanical removal of the endothelium or after the addition of l-NAME (200 μM), and was inhibited by the 5-HT2B/2C receptor antagonist SB 206553 (1 μM), but not the 5-HT2C receptor antagonist SB 242084 (0.1 μM). Endothelium-intact arteries were also relaxed by the selective 5-HT2B receptor agonist BW 723C86 (pD2 7.7). The relaxant response to BW 723C86 was inhibited by 1 μM SB 206553 (pKB 6.8). The low affinity component of relaxation to 5-HT (≥30 nM) remained unaffected after mechanical removal of the endothelium or the addition of l-NAME. In endothelium-denuded arterial rings, 5-HT, 5-carboxamidotryptamine (5-CT), 5-methoxytryptamine (5-MeOT), and frovatriptan produced monophasic relaxations with pD2 values of 6.5, 7.5, 5.9, and 4.7 respectively. Relaxant responses to the agonists were antagonized by the selective 5-HT7 receptor antagonist SB 269970 (pKB 8.2–8.9). The relaxant response to the potent 5-HT7 receptor agonist 5-CT was also antagonized by methiothepin (pKB 9.6), pimozide (pKB 8.2), mesulergine (pKB 7.7), methysergide (pKB 7.4), clozapine (pKB 7.6), and spiperone (pKB 7.4). The estimated pKB values argue in favor of an involvement of 5-HT7 receptors in the direct vasorelaxant action of 5-HT in the pulmonary arteries of weaned pigs. The relaxant response to 5-CT was associated with an increase in cAMP that was surmountably antagonized by SB 269970 (pKB 8.6). The present in vitro bioassay can be used to characterize new drugs with potential agonist or antagonist properties at functional 5-HT7 receptors.

Pharmacological properties of a wide array of ergolines at functional alpha1-adrenoceptor subtypes

Ergot alkaloids act as (partial) agonists or antagonists at serotonergic, dopaminergic and α-adrenergic receptors. In contrast to their affinity at serotonergic (5-HT) and dopaminergic receptor subtypes, only limited information is available concerning their interaction with α-adrenoceptor subtypes. This especially holds true for native α-adrenoceptors. Therefore, we studied the pharmacological profile of 25 ergolines at α1A-, α1B- and α1D-adrenoceptors in vascular rings or strips of rat and guinea pig endowed with these receptors. Contractile responses were studied by measurement of isometric tension changes in rat tail artery (α1A, α1B), guinea pig spleen (α1B) and rat thoracic aorta (α1D). The anti-migraine drugs ergotamine and dihydroergotamine, the anti-parkinsonian drug lisuride and the anti-hyperprolactinemic drug terguride behaved as antagonists or low-efficacy partial agonists at all three α1-adrenoceptor subtypes with nanomolar receptor affinity. Derivatives of these drugs showed lower affinity at α1-adrenoceptors than the parent compounds. Each individual ergoline derivative tested showed low discriminatory capability at the subtypes, α1A, α1B, α1D. A low discriminatory power between the subtypes (α1A, α1B, α1D) seems to be a class effect of the ergolines. The nanomolar affinities of ergotamine, dihydroergotamine and lisuride for α1-adrenoceptors may affect their effectiveness as anti-migraine and anti-parkinsonian drugs, respectively.

Search for influence of spatial properties on affinity at α1-adrenoceptor subtypes for phenylpiperazine derivatives of phenytoin.

A series of phenylpiperazine derivatives of phenytoin was evaluated for their affinity at α(1)-adrenoceptor subtypes in functional bioassays (rat tail artery: α(1A) and/or α(1B); guinea pig spleen: α(1B); rat aorta: α(1D)). The most potent compounds at α(1A)-, α(1B)- and α(1D)-adrenoceptors, 11, 18 and 8, showed affinities in the submicromolar range. The role of a hydrogen bond donor group for affinity and selectivity at α(1B)-adrenoceptors, postulated by Bremners pharmacophore model, was confirmed by functional and molecular modelling studies.