3-Phenylpiperidines. Central dopamine-autoreceptor stimulating activity

Abstract

Thirty compounds related to the selective dopamine-autoreceptor agonist 3-(3-hydroxyphenyl)-N-n-propylpiperidine have been synthesized and tested for central dopamine-autoreceptor stimulating activity. The 3-(3-hydroxyphenyl)piperidine moiety seems indispensable for high potency and selectivity. Introduction of an additional hydroxyl group into the 4 position of the aromatic ring gives a compound with dopaminergic activity but lacking selectivity for autoreceptors. 3-(3-Hydroxyphenyl)-N-n-propylpyrrolidine, 3-(3-hydroxy)-N-n-propylperhydroazepine, and 3-(3-hydroxyphenyl)quinuclidine were all inactive. The most potent compounds were the N-isopropyl-, N-n-butyl-, N-n-pentyl-, and N-phenethyl-substituted 3-(3-hydroxyphenyl)piperidine derivatives. None of the compounds investigated seemed to have central noradrenaline- or serotonin-receptor stimulating activity.

Do autoreceptors mediate dopamine agonist — induced yawning and suppression of exploration? A critical review

“…Recently, considerable efforts have been made to find drugs that are selective agonists on DA autoreceptors (Hacksell et al 1981;And6n et al 1982;Seyfrid et al 1982;Arnt et al 1983;Wickstr6m et al 1985) which have been motivated by reports on clinical effects of low doses of APt, or other DA agonists, on schizophrenia and hyperkinetic disorders (Tolosa and Sparber 1974;Carroll et al 1977;Corsini et al 1977;Smith et al 1977;Tamminga et al 1978;Tolosa 1978;Cutler et al 1983;Meltzer et al 1984). Induction of yawning and, in particular, suppression of exploration have been used extensively for screening purposes.…”

cis-1,2,3a,4,5,9b-Hexahydro-3H-benz[e] indoles: Synthesis and In Vitro Binding Affinity at Dopamine D1 and D2 Receptors

“…The key step in this reaction sequence involved the preparation of the tricyclic enamines 10-14 by the procedures of Evans et a1.12 and Kavadias et al 13 The only products isolated in this reaction were the tricyclic enamines 10-14 in which the double bond is in the six-membered ring in conjugation with the benzene ring. If the double bond had been elsewhere, an olefinic proton would have been observed in the 'H NMR spectra.13 The 1,2,4,5-tetrahydro-3H-benz[e]indoles [10][11][12][13][14] were extremely air sensitive oils and could not be distilled. However, these compounds were stable under a nitrogen atmosphere when stored at 0 "C and were used directly in the synthesis of 15-20 without purification.…”

“…IR spectra were (t, 3 H, CH,), 1.61 (m, 2 H, CH,CH,), 2.22-3.10 (m, 6 H, ArCH,CH, and NCH,), 3.78 (s, 3 H, OCH,), 5.19 (s, 1 H, ArCH=C) sensitivity. These compounds were used directly in the synthesis of [10][11][12][13][14] (method B). The following compounds were synthesized by method A.…”

“…A 1 : 1 mixture of Et,O and benzene (100 mL) was added, and the aqueous phase was extracted with Et,O (100 mL). The combined organic phase was washed with H,O (2 x 10 mL), dried (Na,SO,), and evaporated to give 6.8 12) and the compounds were used directly in the synthesis of 15-20. 3 Method C: Synthesis of cis-6-Methoxy-3-(n-propyl)-1,2,3a,4,5,9b-hexahydro-3H-benz[elindole (15) with Platinum Oxide in Ethanol-The enamine 10 3 H, OCH,), 6.68 (m, 3 H, ArH); "C NMR (CDCl,, 300 MHz): 6 12.2 (NCH&H,CH3), 19.1 (C-5), 22.0 (NCH,CH,CH,), 25.5 (C-4), 33.6 (C-l), 41.0 (C-gb), 52.9 (C-2), 56.7 (NCH,), 62.1 (C-3a), 106.8 (C-7), 120.9 (C-9), 126.2 (C-B), 126.3 (C-5a), 142 (C-ga), and 156.4 (C-6); MS: mlt 245 (M+).…”

Synthesis and biological activity of cyclohexylamine derivatives

“…The class of cyclohexylamine derivatives includes acetylcholinesterase inhibitors [1,2], activators of dopamine receptors in the CNS [3], and highly active k-opioid analgesics [4]. The discovery of the psychotomimetic action of the well-known analgesic drug phencyclidine [5] has expanded investigations devoted to the synthesis and pharmacological characterization of various derivatives of cyclohexylamine [6 -10].…”