Stereoselective Interaction of Mianserin with 5-HT3 Receptors

Abstract

The interaction of the enantiomers of mianserin with the 5-HT3 receptor was determined. Using [3H]granisetron binding, (-)-mianserin was more potent than (+)-mianserin (pKi 8.46 and 6.95, respectively). The enantiomers competitively antagonized the depolarizing effect of 5-hydroxytryptamine in the rat vagus nerve preparation (pKapp: (-)-mianserin 8.13, (+)-mianserin 6.58). This stereoselectivity was maintained in-vivo as determined using ex-vivo inhibition of [3H]granisetron binding. Therefore, in contrast to its enantiomeric selectivity for the 5-HT1C and 5-HT2 receptors, where the (+)-isomer is more potent, the enantiomeric selectivity of mianserin for the 5-HT3 receptor was reversed. This differential selectivity of the enantiomers of mianserin may be useful in elucidating its utility in anxiety states.

Multiple 5‐HT receptors in the guinea‐pig superior cervical ganglion

“…Likewise the low affinity of mianserin (pKapp=5.4) in guinea-pig SCG contrasts dramatically with its high affinity for rat 5-HT3 receptors (Wood et al, 1993 (Newberry et al, 1991 (Cadogan et al, 1993).…”

“…The antidepressant drug, mianserin, has been shown to interact with a variety of 5-HT receptors (Wood et al, 1993 (Toth & Shenk, 1994 (compare Julius et al, 1990;Watts et al, 1994).…”

“…We have extended the pharmacology of this response with other 5-HT3 receptor antagonists, namely granisetron (Sanger & Nelson, 1989), BRL 46470 (Blackburn et al, 1992) and mianserin (Wood et al, 1993) (see Figure 2). Granisetron (0.1 /M) produced a parallel rightward shift of the CRC to 2-methyl-5-HT with an apparent affinity (pKapp) of 7.7.…”

Enantiomeric antidepressant drugs should be considered on individual merit

“…However, one notable exception is the R-( À )-enantiomer's higher af®nity for the 5-HT 3 receptor, suggesting that the racemic mixture may represent an advantage over the pure active enantiomer, due to the potential antiemetic bene®ts of blocking this receptor (Wood et al, 1993).…”

“…Compared with the R-( À )-enantiomer, the S-( )-enantiomer of mianserin is considerably more active in a number of different pharmacological assays, such as noradrenaline reuptake inhibition, presynaptic 2 -adrenoceptor antagonism (Pinder, 1985) and binding af®nity for most 5-HT receptor subtypes (5-HT 1A , 5-HT 1B , 5-HT 2C , 5-HT 2A ) (Wood et al, 1993). However, one notable exception is the R-( À )-enantiomer's higher af®nity for the 5-HT 3 receptor, suggesting that the racemic mixture may represent an advantage over the pure active enantiomer, due to the potential antiemetic bene®ts of blocking this receptor (Wood et al, 1993).…”