kosteric repiacement of -C&- by -O- The crystal sIrucIure’ conformation of the f - t -l@oxa malope @bsuiure configure- tton 5) of (+ Fmianserin fabsolute config- uration S) is raIher unexpected. In Fig. 1 ~hc +.uperimposiIion of Ihe trystal structure con&matrons of mi; lserin and its I@oxa analogue is shoun. II .s clearly seen that the stalled classical isosters -SHz- and-Q do in facl fead IO remarkable structural differ- teF$ in the solid state. Whereas both arcmzic rings of mianserin are in an eqratoria! position of the &era&e ring. it is seer, that in Ik oxaanakgue the pheflyl at Ns is in art axial position. The electron IoEe pairof the bridge-head :US atom and the H atOm at CM are m a mum con&ration in rmarI+etin rskereas a 6%~ c~~~~ is &&‘ved in fhe ti3-caa analogue. The angle brtween Ox planes rhrough the phenol rings is I 15’ in dve oxa-aflalogue. The cor- respn;ding angle in mianserin is 106’.

From an N%fR %I@‘. it *as concluded that Abe free-base of the I@oxa analopue in

CD&; exhibited a:rclrzs configuralion for the NS tone pair and the H atom at CM.

it was concluded that the energy d#er- ence between the cir and WAS configure. Iion is small for Ihese tetracyclic com- pounds and that more structurally rigid analogues have to be synthesized and tesIed IO establish the biologically relevant con- iormarion.

The comparison between mianserin and its IO-oxa analogue quite clearly shows the danger of solely relying on X-ray crystai- lographic techniques todetermine the shape of a molecule. As the authors do. on:: should supplement X-ray crystal stTucturc: information with structural informatio!\ derived from measurements in the disso!.. ved or liquid state and possibly from Ibeo~tical calculations,

II is thus instructive to note that at a fust sight (the classical Zdimensional represen. tation of chemical structures) harmless ‘isosteric’ replacement of -CHZ- by -O- leads. at least in these tetracyclic structures. I:O rather unexpected structural differences.

Reading list

I P TOLLENAERE

Memory rn~u~~t~o~~ the sYm@athoadrenaI system and the &e&t of drugs S#uzrly after training. memoe is trmsr hrmed from a labile infoa stable state. i-his is called consolidation. Being labile means thaw n IS susceptible to a variety of external and mIemal intluences. The former are belie& tct act through the latter. and the &II&% involve rteurohumoral and hormonal chges caused b: arousal or orher non- *pecifK comequeme~ of training? =.

AWrsivetrainmg. Iikeaa> 0tbe~sIressful situation. is us&f) believed to bz accom- panied b! a stimul;uron oi the ~krnpatho. adrenai s~%ml Ihal. in mm. ma> mod&W brain processes essmtlal ior snnsolidation %xigh &e:5. a_-tions: for example. &inge m blood Fesiurs or in regional cerebral bfood Ilo-A that ma? affea the a&it> oi tk m#rtmin reticular formarion or of o~ber brain regions’ ‘~ However. char@5 in per&&rat adrenaline or 83or- adrenaline kveis caus+ by tining have acitIa& been measure45 only recently*2.

Gold and McCarty* placed rais in a small lighted compamnent from which they could enter an adjacent larger, dark com- panment. When they did so they received a fixMock. When piaced again in the lighted stan-box the next day. animals generally refrained from entering the dark side; this uas raken as a measure of memory. Immediate post-training srimulation of the fromal conex through indwelling eiec- Irodes impaired memo0 . Plasma adrenaline and noradrenaline levels were rniasured0.5. 10.2Uand4Omin after sim- pie exposure of the rats to the apparams (no foctl~hocks). after avoidance training (u ith footshock), after stimulation of the frontal cortex. and afrer Iraining followed by stimulation. All groups showed an immedi- ate increase of bfood adrenaline levels. and all except the exposed group showed an increase of b&xl noradrenaline levels. The effect uas most mtense in Ibe animals sub.

mined to training u-ith or rcithour cortical stimulalion. Catecholamine levels returned IO normal in 5-10 min in the trained groups. Frontal cortex stimulation prolonged the refurn of plasma CaIeeholami~es to normal baseline values, probably btcsuse the pro- cedure made blood flow slower. The find- ings suggest that circulating adrenaline (which comes mainly from the adrenal glands) and nora~enaii~e fu hich origi- nates maicly in sympathetic nerve endings) are elevated by training. thar the effecr is not specific to learning. and rhat the amnes tic influence of frontal corkx stimulation is not mediated by the s~mpathoadrenai sys- tern*. However. the effect of other post- training treatments. such as the i.p. injec- tion of vasopressin. which enhances. and Met-enkephalin. uhich depresses. memory consolidation is strongly attenuated by adrena meduIlecIomy and reinstated by the systemic administration of adrenaline (see Ref. 3). This suggests thaI these ueatments do not act through Ihe adrenal medullae. but that they require the con~miIant presence of peripheral adrenaline in order to be effec- tive; or. in other words. tbat adrenal medul-

lary secretion may be important for mcm- ory modulation as a cooperative or con- comitant factor.

Drugs that affect t le functioning of the symprthoadrenal system. such as tyramine and guanethidine, may alter memory when given shortly before or after training”. To this list we may have to add D amphetamine, long believed to be a sub stance that exerted rts behavioral effects centrally. The post&mung i.p. administra tion of 220-330 pg per rat of D amphetamine sulfate improved retention of a task similar to the oae described above; the i.c.v. administration of SO-500 pg per rat, however, had no effect on memory, even though it was able to induce dose dependent changes in locomotor activity’. This clearly separates the memory- enhancing effect of amphetamine from its

general rcntral stimulant action. and xug- gestx that the former is not crntmlly medi- ated. In animals pretreated with 6- OH-dopamine t.v., which reduced heart hut not brain noradrenaline levels by 7587%. there was a four-fold increase in sensitivity to the memory enhancing effect of i.p. amphetamine which may be explained of course. by peripheral nor- adrenaline receptor supersensitivity~.

Taken together, these tindings suggest an important role for the sympathoadrenal system in the modulation of memory con- solidation and the effect of drugs there- upon Whether this role is mediated by reflex changes in brain activity caused by vascular changes or by some other factor. is not known. Selective penetration of the amines at restricted brsin sites, such as the area postrema. cannot be ruled OCI’.

News from the BUPHAR section on toxicology At the July 1981 General Meeting, the fol- lowing indimriduals were elected IO the Executive Board: Chairman - G. L. Plaa (Canada); Vice-Chairman - F. Sakai (Japan); Secretary-D. S. Davies (U.K.); Treasurer-G. C. Petri (Italy); Councillors - E. Alhawa (Finland), J. R. Gillette (U.S.A.), J. A. Castro (Argentina), 0. Benesova (Czechoslovakia) and F. Oesch (F.R.G.).

The Section has grown considerably in membership since its inception; there am now 542 members. In the past, only adher- ents of an IUPHAR society could join the Section. However, Article 3 of the bye laws of the Section was amended and the Executive Board can now accept as Mem hers of the Section on Toxicology qualified scientists who are not members of an IUPHAR society. Such applications are evaluated on the basis of a curriculum vitae and must be approved by a two-thirds

majority of the Executive Board. The Section has sponsored or cospon-

sored several scientific activities in the last 3 years: Workshop on Rat EEG (Zurich); Symposium on Chemical Indices and Mechanisms of Organ Directed Toxicity (Barcelona); Workshop on the Application of Behavioral Pharmacology and Toxicol- ogy (Capri). All were very successful.

Professors Zbinden and Davies completed a toxicology lecture+xpertise tour in Chile and Argentina in October-November I98 I. This tour was sponsored by IUPHAR as a responsibility of the Section on Toxicol- ogy. The programme was very well received and the Section would like IO pres- ent a similar one elsewhere in the future. Anyone wishing to propose such an educa tional exercise should contact the Chairman or the Secretary.

The Executive Board is presently in communication with the Programmr

Committee oi the 1984 IUPHAR Conpre\s regarding symposia and lectures on to~tcol- ogy for inclusion in the London Congress. A number of excellent tttlrs have heen submitted for constderatinn.

The Section is interestsd in supp,ninp locally orgmized norkxhops. regtonal meetings and educational activities ot rori- colopical mterest. Some veq hmited financial &stance is avadahle. Interested parttrs should snd a brief outline of then proposal 1%) the Chairman or Secrerdr! lor consideratton.

Addres,es: Pr,>f. G. L. Ptaa. Faculrr dch titudes \up&ieurex. Universitr de Xlontreal. C.P. hl28. 5uccursals .a. Monrredl. Quebec, Canada H3C 357. Prof. D. S. Davies. Department of C~illli‘d~ Phar- macolog> Royal Postgraduate Xlcdtcal School. Ducane Road. London WI? OHS. U.K.