Stimulus properties of arylpiperazines: NAN‐190, a potential 5‐HT_1A serotonin antagonist

Abstract

Glennon, R.A., N.A. Naiman, M.E. Pierson, M. Titeler, R.A. Lyon, J.L. Herndon, and B. Misenheimer: Stimulus properties of arylpiperazines: NAN-190, a potential 5-HTlA serotonin antagonist. Drug Dev. Res. 16:335-343, 1989.Arylpiperazines have been demonstrated to bind both at 5-HT,* and 5-HTlB serotonin receptors. In an attempt to design novel 5-HTIA agonists and antagonists, based on an arylpiperazine nucleus, we investigated the stimulus properties of a series of such agents (in rats trained to discriminate 0.5 mgikg of the 5-HTlB agent TFMPP from saline) to determine what structural features were important for 5-HTIB activity. This done, we modified these agents to eliminate those features and, at the same time, incorporated structural features that appeared important for 5-HTIA affinity. The resulting agents displayed high affinity for 5-HTlA sites. One agent in particular, neither mimicked nor antagonized the TFMPP stimulus, but was capable of antagonizing the stimulus produced by the 5-HTIA agonist 8-OH DPAT (0.2 mgikg). These preliminary results suggest that NAN-190 may be a potential 5-HTIA antagonist.

Pindolol does not act only on 5-HT 1A receptors in augmenting antidepressant activity in the mouse forced swimming test

“…Median immobility time (s) of saline controls: 234 (205239) Results expressed as median immobility time (s) with minimum and maximum values in parentheses **P < 0.01 versus control, ++ P < 0.01 versus drug alone (Steels test for non-parametric data, n = 10). Median immobility time (s) of saline controls: 233 (223 239) a¦inity for the 5-HT 1A receptor and has been shown to act as a presynaptic 5-HT 1A receptor antagonist in vivo (Glennon et al 1988(Glennon et al , 1989Chojnacka-Wojcik et al 1991;Millan et al 1993b). It has also been suggested that NAN 190 has a weaker activity at the postsynaptic than at the presynaptic 5-HT 1A receptor (Done and Sharp 1994).…”

Serotonin involvement in the discriminative stimulus effects of κ opioids in pigeons

“…For example, 8-OH-DPAT produces spontaneous tail flicks in rats and these effects are blocked by pre-treatment with NAN-190 (Millan et al 1991). NAN-190 also blocks the discriminative stimulus effects of 8-OH-DPAT in rats (Glennon et al 1988(Glennon et al , 1989.…”

“…The serotonergic compounds examined here vary in their selectivity for different serotonin receptor subtypes. These include 8-OH-DPAT, currently the most selective agonist available for the 5HTtA receptor (Middlemiss and Fozard 1983;Hjorth 1991); NAN-190, a 5HT1A post-synaptic antagonist (Glennon et al 1988(Glennon et al , 1989 and 5HT~A presynaptic partial agonist (Hjorth and Sharp 1990); two 5HT1A partial agonists, buspirone and ipsapirone (Peroutka 1985;Bockaert et al 1987); ketanserin, which is relatively selective for the 5HT 2 receptor (Leyson et at. 1982); MDL72222, a selective 5-HT 3 receptor antagonist (Fozard 1984;Tyers 1990); mCPP, a 5HT1B,~c agonist (Sills et al 1984;Kennett and Curzon 1988) and DOI, a 5HT 2 agonist (Glennon 1986;Schmidt and Peroutka 1989).…”

Anxiety-induced antinociception in mice: effects of systemic and intra-amygdala administration of 8-OH-DPAT and midazolam

“…In order to investigate the potential involvement of amygdaloid 5-HT 1A receptors in antinociception and anxiety, mice were bilaterally microinjected with either 8-OH-DPAT or NAN-190, a 5-HT 1A antagonist (Engel et al 1986;Sprouse et al 1987;Glennon et al 1988aGlennon et al , 1988bGlennon et al , 1989, into the amygdala. The results showed that neither 8-OH-DPAT nor NAN-190 significantly altered OAIA ( Fig.…”