Spiperone:  Influence of Spiro Ring Substituents on 5-HT_2ASerotonin Receptor Binding

Abstract

Spiperone (1) is a widely used pharmacological tool that acts as a potent dopamine D2, serotonin 5-HT1A, and serotonin 5-HT2A antagonist. Although spiperone also binds at 5-HT2C receptors, it is one of the very few agents that display some (ca. 1000-fold) binding selectivity for 5-HT2A versus 5-HT2C receptors and, hence, might serve as a useful template for the development of novel 5-HT2A antagonists if the impact of its various substituent groups on binding was known. In the present investigation we focused on the 1, 3,8-triazaspiro[4.5]decanone portion of spiperone and found that replacement of the N1-phenyl group with a methyl group only slightly decreased affinity for cloned rat 5-HT2A receptors. However, N1-methyl derivatives displayed significantly reduced affinity for 5-HT1A, 5-HT2C, and dopamine D2 receptors. Several representative examples were shown to behave as 5-HT2 antagonists. As such, N1-alkyl analogues of spiperone may afford entry into a novel series of 5-HT2A-selective antagonists.

Ketanserin and Spiperone as Templates for Novel Serotonin 5-HT2A Antagonists

“…The first region of the spiro ring to be addressed was the N 1 -phenyl substituent [20]. Interestingly, the N 1 -cyclohexyl derivative 45 (Table 5) had a binding profile similar to that of spiperone.…”

“…It appeared that a substituent smaller than isopropyl but larger than -H was necessary. The smaller N 1 -alkyl derivatives (i.e., methyl, ethyl) were examined and the N 1 -methyl compound 48 (KML-010) was identified as a reasonable compromise [20]. Although 48 binds at 5-HT 2A receptors with 10-fold lower affinity than spiperone, it lacks affinity for 5-HT 2C and 5-HT 1A receptors, and its affinity for D2 dopamine receptors is 400-fold lower than that of spiperone.…”

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

“…1982;Kovacs and de Wied 1978;Seliger 1975;Seliger 1977). Remoxipride (3-10 mol/kg) produced a decrease in general motor activity and a profound increase in training latencies without any effect on PA retention; whereas, raclopride affected neither PA training nor retention performance.Unlike remoxipride and raclopride, spiperone (two times higher affinity for DA D 2 receptors than for the 5-HT 2A receptors) (Leysen et al 1993;Metwally et al 1998) produced an impairment of PA retention at the 0.1 mg/ kg dose, which is at the threshold for induction of catalepsy (Hess et al 1988). Interestingly, the doses of spiperone (0.03 mg/kg IP), remoxipride (3 mol/kg SC), and raclopride (0.1-0.3 mol/kg IP) used in the combination studies with PCA or 8-OH-DPAT have been reported to block DA agonist-induced hyperactivity (Magnusson et al 1986;Ögren 1996;Ögren and Archer 1994;Ögren et al 1990;, thus indicating DA (predominantly, D 2 ) receptor antagonism in vivo, albeit devoid of apparent catalepsy.…”

Synthesis of Novel Trispiroheterocycles through 1,3‐Dipolar Cycloaddition of Azomethine Ylides and Nitrile Oxide

“…Pyrrolidine, 1-3 isoxazoline [4][5][6] and piperidine [7][8][9] substructures exhibit important biological activities. The 1,3-dipolar cycloaddition of nitrile oxides to azomethine ylide to alkenes affords pyrrolidines and isoxazolines.…”