Involvement of the bed nucleus of the stria terminalis activated by the central nucleus of the amygdala in the negative affective component of morphine withdrawal in rats.

The central nucleus of the amygdala (Ce) and the bed nucleus of the stria terminalis (BST) are key structures of the extended amygdala, which is suggested to be involved in drug addiction and reward. We have previously reported that the Ce plays a crucial role in the negative affective component of morphine withdrawal. In the present study, we examined the involvement of the neural pathway between the Ce and the BST in the negative affective component of morphine withdrawal in rats. Rats were rendered morphine dependent by s.c. implantation of a 75-mg morphine pellet for 3 days, and morphine withdrawal was precipitated by an i.p. injection of naloxone (0.3 mg/kg). In the place-conditioning paradigm, discrete bilateral excitotoxic lesions of the Ce or the BST significantly reduced naloxone-precipitated morphine withdrawal-induced conditioned place aversion. On the other hand, they had little effect on morphine withdrawal-induced somatic signs. In an immunohistochemical study for c-Fos protein, naloxone-precipitated morphine withdrawal dramatically induced c-Fos-immunoreactive neurons in the capsular part of the Ce, and the lateral and medial divisions of the BST. Bilateral excitotoxic lesion of the Ce reduced the number of morphine withdrawal-induced c-Fos-immunoreactive neurons in the lateral and medial BST, with significant decreases in the posterior, ventral and juxtacapsular parts of lateral division, and anterior part of the medial division, but not in the ventral part of the medial division of the BST. On the other hand, bilateral excitotoxic lesion of the BST had no effect on such c-Fos induction within the capsular part, nor the ventral and medial divisions of the Ce. These results suggest that activation of the BST mediated through the neural pathway from the Ce contributes to the negative affective component of morphine withdrawal.

Dynamics for reaction of an ion pair in aqueous solution: reactivity of carboxylate anions in bimolecular carbocation-nucleophile addition and unimolecular ion pair collapse.

[reaction: see text]. The sum of the rate constants for solvolysis and 18O-scrambling of 4-MeC6H4(13)CH(Me)18OC(O)C6F5 in 50/50 (v/v) trifluoroethanol/water, k(solv) + k(iso) = 1.22 x 10(-5) s(-1), is larger than k(solv) = 1.06 x 10(-5) s(-1) for solvolysis of the unlabeled ester. This shows that the ion pair intermediate undergoes significant internal return. The data give k(-1) = 7 x 10(9) s(-1) for internal return by unimolecular collapse of the ion pair, which is significantly larger than k(Nu) = 5 x 10(8) M(-1) x s(-1) for bimolecular nucleophilic addition of carboxylate anions to 4-MeC6H4CH(Me)+.

Concurrent induction of two chiral centers from symmetrical 3, 4-disubstituted and 3,3,4-trisubstituted 4-pentenals using Rh-catalyzed asymmetric cyclizations

Asymmetric cyclization of symmetrical 3,4-disubstituted and 3,3, 4-trisubstituted 4-pentenals was studied using Rh-complexes with chiral ligands. The cyclization of symmetrical 4-pentenals 4a,b by a neutral Rh[(R)-BINAP]Cl afforded cis-3,4-disubstituted (4R)-cyclopentanones 9a,b of >95% ee in 25-31% yields; on the other hand, the cyclization of 4a-c by a cationic Rh[(R)-BINAP]ClO(4) afforded trans-3,4-disubstituted (4S)-cyclopentanones 10a-c of >95% ee in 70-81% yields. All stereoisomers could be stereoselectively made by the selection of a neutral or cationic Rh-complex, and (R)- or (S)-BINAP ligand. The Rh-catalyzed cyclization could be applied to the construction of cyclopentanones 17 and 18 bearing a chiral quaternary carbon. The cyclization by the cationic Rh[(R)-BINAP]ClO(4) afforded the optically active trans-3,3, 4-trisubstituted cyclopentanones 18a-c of 92-95% ee in 75-83% yields. The catalytic cycle was also studied by using deuterium aldehyde, and the tentative mechanisms of the enantio- and diastereoselection were proposed.

N-[[1-(2-phenylethyl)pyrrolidin-2-yl]methyl]cyclohexanecarboxamides as selective 5-HT1A receptor agonists.

A series of benzamides was synthesized as selective agonists for the 5-HT1A receptor. It was found that (S)-N-[[1-(2-phenylethyl)pyrrolidin-2-yl]methyl]cyclohexanecarb oxamide(7-(S)) has potent and selective agonistic activity for the 5-HT1A receptor (5-HT1A; Ki 0.49 nmol/L, D2; IC50 = >1000 nmol/L, 5-HT2; Ki = 240 nmol/L).

Unexpectedly small ortho-oxygen substituent effects on stabilities of benzylic carbocations.

Equilibrium constants are reported for the ionization of benzylic alcohols to carbocations stabilized by cyclic or acyclic o-alkyl or o-oxygen substituents. The measurements were stimulated by the observation of small or inverse effects of replacement of an o-CH2 group by O or S in the cyclopentyl ring of indanol (kO/kCH2 = 1.2) or in the cyclohexyl ring of tetralol (kO/kCH2 = 0.6, kS/kCH2 = 0.3) on rates of carbocation formation. Values of pKR (KR = [ROH][H+]/[R+]) have been obtained by combining rate constants, kH, for the acid-catalyzed ionization of the alcohols with kH2O for attack of water on the carbocation measured by the azide clock method. For carbocations derived from the following alcohols, values of pKR are as indicated: 1-indanol, -11.7; 2,3-dihydro-3-hydroxybenzofuran (benzofuran hydrate), -9.3; 1-tetralol, -12.2; 4-chromanol, -12.0; 4-thiochromanol, -12.3; o-methyl-1-phenylethanol, -13.8; o-methoxy-1-phenylethanol, -11.7. The measurements show that, in contrast to its small kinetic effect, the equilibrium effect of replacing the o-CH2 group by O in the cyclopentyl ring of indanol is 250-fold, whereas the effect of the same replacement in the cyclohexyl ring of tetralol is only 1.6. It is concluded (a) that the efficiency of conjugation of annular o-oxygen substituents to a benzylic carbocation center is sensitive to conformational restrictions arising from ring strain and (b) that, in the case of indanol, the kinetic effect of the same oxygen atom is subject to an imbalance of favorable resonance and unfavorable inductive effects at the transition state.

N-[1-(2-Phenylethyl)pyrrolidin-3-yl]-1-adamantanecarboxamides as novel 5-HT2 receptor antagonists.

A series of 1-adamantanecarboxamides was synthesized and examined for their potency as a selective 5-HT2 receptor antagonist. We found (S)-N-[1-[2-(4-fluorophenyl)ethyl]pyrrolidin-3-yl]-1-adamantane carboxamide hydrochloride hydrate (10-(S), Y-39241) to have a high affinity and selectivity for 5-HT2 receptors, and this potent anti-platelet effect of Y-39241 was confirmed both in vitro and in vivo.