3308-93-8

Upstream product

• 3308-95-0 2-(4-fluorophenyl)-2-(3-phthalimidopropyl)-1,3-dioxolane 
• 3874-54-2 4-(4-fluorophenyl)-4-oxo-n-butyl chloride 
• 3308-94-9 4-chloro-1-(4-fluorophenyl)-1,1-(ethylenedioxy)butane 
• 660844-86-0 2-(3-azidopropyl)-2-(4-fluorophenyl)[1,3]dioxolane 

Downstream Products

• 22217-86-3 2-(4-fluorophenyl)-Δ¹-pyrrolidine 
• 839677-32-6 1-{3-[2-(4-fluorophenyl)-1,3-dioxolan-2-yl]propyl}-4,4-diphenyl-4-silapiperidine 
• 1314110-88-7 N-(4-(4-fluoro)butyrophenone)-4-azahexacyclo[5.4.1.0^2,6.0^3,10.0^5,9.0^8,11]dodecan-3-ol 

Relevant academic research and scientific papers

Syntheses and hypotensive properties of substituted 2-aminotetralins

The synthesis and activity in the spontaneously hypertensive rat of several 4-(1,2,3,4-tetrahydronaphthyl-2-amino)-1-(4-fluorophenyl)-1-butanones is reported. Maximal antihypertensive activity was associated with 5,6-dimethoxy substitution in the aminotetralin moiety.

Molecular hybridization of 4-azahexacyclo[5.4.1.02,6.0 3,10.05,9.08,11]dodecane-3-ol with sigma (σ) receptor ligands modulates off-target activity and subtype selectivity

A series of N-substituted 4-azahexacyclo[5.4.1.02,6.0 3,10.05,9.08,11]dodecan-3-ols incorporating the respective arylalkyl subunits from several known sigma (σ) receptor ligands were synthesized and evaluated for their affinity against σ receptors and dopamine receptors. The hybrid trishomocubane-derived ligands (4-6) showed good selectivity for σ1 and σ2 receptors over multiple dopamine receptors. The molecular hybrid obtained from haloperidol and 4-azahexacyclo[5.4.1.02,6.03,10.0 5,9.08,11]dodecan-3-ol (4, σ1 K i = 27 nM, σ2 Ki = 55 nM) showed reduced affinity for D1-D5 dopamine receptors when compared to haloperidol itself. The compound with the greatest σ1 affinity in the series, benzamide 4 (σ1 Ki = 7.6 nM, σ2 Ki = 225 nM) showed a complete reversal of the subtype selectivity displayed by the highly σ2 selective parent benzamide, RHM-2 (3, σ1 Ki = 10412 nM, σ2 Ki = 13.3 nM).

Design, Synthesis, and Evaluation of Metabolism-Based Analogues of Haloperidol Incapable of Forming MPP+-like Species

The long-term, irreversible, Parkinsonism-like side effects of haloperidol have been speculated to involve several mechanisms. More recently, it has been speculated that the metabolic transformation to MPP+-like species may contribute to the Parkinsonism-like side effects. Because BCPP+ and its reduced analogue have been shown to possess the potential to destroy dopamine receptors in the nigrostriatum, we have designed new analogues of haloperidol lacking the structural features necessary to form neurotoxic quaternary species but retaining their dopamine-binding capacity. The most potent agent at the D2 receptor, the homopiperidine analogue 11, was found to be equipotent to haloperidol. It was also of interest to identify analogues with DA binding profiles similar to that of clozapine at the dopamine receptor subtypes. Evaluation of the proposed agents shows that the ratio of D2 to D4 (2) binding of clozapine was mimicked by 7 [Ki(D2) = 33, Ki(D3) = 200, Ki(D4) = 11 nM; Ki(D2)/Ki(D4) = 3] and 9 [Ki(D2) = 44, Ki(D3) = 170, Ki(D4) = 24 nM; Ki(D2)/Ki(D4) = 2]. A preliminary in-vivo testing of compound 7 shows that its behavioral profile is similar to that of clozapine. This profile suggests that there is a need for further evaluation of these two synthetic agents and their enantiomers for efficacy and lack of catalepsy in animal models.

Antagonism of 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane stimulus with a newly identified 5-HT2- versus 5-HT(1C)-selective antagonist

DOM [i.e., 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane] is a 5- HT(1C/2) serotonin agonist that exerts stimulus control of behavior in animals. In order to determine if the discriminative stimulus effect of DOM is 5-HT(1C)- or 5-HT2-mediated, it would be informative to conduct tests of stimulus antagonism with a 5-HT(1C)- or 5-HT2-selective antagonist. To date, no such agents exist. Although the neuroleptic agent spiperone binds at D2 dopamine receptors and 5-HT(1A) serotonin receptors, (a) it displays about a 1000-fold selectivity for 5-HT2 versus 5-HT(1C) sites and (b) it has been used as a '5-HT2-selective' antagonist. Because spiperone is a behaviorally disruptive agent, it is not suitable for use in drug-discrimination studies. Using the spiperone molecule as a starting point, a limited structure- affinity investigation was conducted in order to identify a suitable antagonist with high affinity and selectivity for 5-HT2 receptors, and yet an antagonist that might lack the disruptive actions of spiperone. Various modifications of the spiperone molecule were examined, but most resulted in decreased 5-HT2 affinity or in loss of selectivity. One compound, 8-[3-(4- fluorophenoxy)propyl]-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (26), was shown to bind at 5-HT2 sites with high affinity (K(i) = 2 nM) and >2,000- fold selectivity versus 5-HT(1C) sites. In tests of stimulus antagonism using rats trained to discriminate 1 mg/kg of DOM from saline vehicle, 26 behaved as a potent antagonist (ED50 = 0.003 mg/kg) and lacked the disruptive effects associated with spiperone. As such, (a) it would appear that the DOM stimulus is primarily a 5-HT2-mediated, and not 5-HT(1C)-mediated, phenomenon, and (b) compound 26 may find application in other pharmacologic investigations where spiperone may not be a suitable antagonist.