Resolved 3-(3-Hydroxyphenyl)-N-n-propylpiperidine and its analogs: central dopamine receptor activity

Abstract

Seven enantiomeric pairs of N-alkyl analogues of 3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP, 12) have been synthesized and evaluated pharmacologically (biochemistry and behavior) in order to examine their ability to interact with central dopamine (DA) receptors, particularly DA autoreceptors. In the R series it seems as if all compounds behave as classical DA receptor agonists with affinity and intrinsic activity for both pre- and postsynaptic receptors. The same bifunctional profile seems to be valid for the S enantiomers with N-substituents larger or bulkier than n-propyl. Likewise, the S enantiomers with ethyl or n-propyl N-substituents seem to have affinity for both pre- and postsynaptic receptors. In the total series, (S)-(-)-3-PPP [(S)-12] seems to be the most interesting compound both from the theoretical and the therapeutical point of view, possibly attenuating DA function in two different ways by stimulating the presynaptic receptors and blocking the postsynaptic receptors. This compound has been selected for extended pharmacological studies as a potential antipsychotic drug.

Asymmetric Suzuki-Miyaura coupling of heterocycles via Rhodium-catalysed allylic arylation of racemates

“…To demonstrate the method can be used to synthesize valuable molecules we prepared the antipsychotic drug preclamol44 whose asymmetric synthesis has recently been reported using powerful methods4546. Using standard conditions for piperidene derivatives, 81 which had been previously converted to preclamol47, was prepared from 3-MeO-Ph boronic acid in three steps in 64% overall yield and 96% ee (Fig. 5b).…”

Dopamine receptor agonists: Mechanisms underlying autoreceptor selectivity II. Theoretical considerations

“…While apomorphine (Waiters and Roth, 1976;Hjorth etal., unpublished findings) and (+)-3-PPP completely reverse the GBL-induced elevation of striatal DA synthesis rate, (-)-3-PPP produces only a 650/0 reversal (Clark et aL, 1984 a). Classical drug receptor theory predicts that a partial agonist would reduce the effect of a full agonist or act to produce additive agonistic effects given the relative concentrations of the two substances competing at common receptor sites.…”

“…The drug reduces the gamma-butyrolactone (GBL)-induced increase in DA synthesis rate, an effect which is stereospecifically blocked by the DA-receptor antagonist (+)-butaclamol (Hjorth et al, 1983(Hjorth et al, , 1984(Hjorth et al, b, 1985Clark et a/., 1984 a). In addition, (-)-3-PPP reduces the increase in DA synthesis rate produced by reserpine (an action which is blocked by haloperidol) or an acute hemitransection of the brain (Hjorth, 1983;Hjortb et aL, 1983Hjortb et aL, , 1984Magnusson et al, 1983).…”

“…In each example, the effect of (-)-3-PPP could be explained in terms of the relative concentrations of drug and endogenous DA at a common DA receptor. However, (-)-3-PPP exhibits 650/o intrinsic activity (relative to apomorphine and (+)-3-PPP) at DA autoreceptors controlling DA synthesis in the GBL and 4 hours reserpine models, while possessing 90-95O/o intrinsic activity at these receptor sites in animals with an 18 hours reserpine pretreatment (Hjorth et al, 1983;Clark et al, 1984 a;Hjorth et al, 1984 a). Classical receptor theory would not predict a difference in intrinsic activity of(-)-3-PPP in the 4 and 18 hour reserpine models since in neither case is DA present to interact with the drug at DA autoreceptors.…”

Reactivity and stereoselectivity of oxazolopyridines with a ring‐junction nitrogen atom

“…Hydrogenolysis of aryl piperidinone 106 with H 2 , Pd (OH) 2 /C in the presence of Boc anhydride followed by hydrolysis of the formed N ‐protected piperidine 108 , furnished the desired piperidine 109. Another route for the preparation of drug (−)‐3‐PPP (preclamol) ( 110 ) was reported by Wikstrom et al by alkylation of 109 followed by methyl group hydrolysis (Scheme ).…”