Potential CNS DrugsExperimental Biology 2005 Meeting

San Diego, CA, USA. April 2 – 6, 2005

Alexander Scriabine

Department of Pharmacology, Yale University School of Medicine, New Haven, CT, USA

The experimental Biology 2005 meeting was held at the Convention Hall in San Diego,

CA, USA, April 2 – 6, 2005 jointly with the XXXV International Congress of Physio-

logical Sciences. It consisted of 1024 sessions, each session had 3 to 25 oral presentations

or posters. More than 10, 000 scientists attended the meeting. This report covers only pre-

sentations or posters, attended or viewed by the author of this report, that deal with the ac-

tivity of new or potential drugs affecting the central nervous system.

Antidepressants

E. M. Jutkiewicz et al. (Univ. of Michigan, Ann Arbor, MI, USA; NIH, Bethesda,

MD, USA; and Ardent Pharmaceuticals, Durham, NC, USA) described a novel nonpepti-

dic ä-opioid agonist, DP1287, with antidepressants-like activity. At 1 mg�kg s.c. and

higher doses DP1287 decreased immobility of rats in forced swim test and increased loco-

motor activity. The behavioral effects of DP1287 were blocked by naltrindole. DP1287

had no convulsant activity at doses up to 100 mg�kg s.c., but by i.v. administration pro-

duced convulsions even at 1 mg�kg. The difference in the convulsant activity of DP1287

by different routes of administration is explained by poor and slow absorption of the drug

by s.c. route of administration. A rapid rate of receptor activation is required to produce

convulsions, but not for antidepressant activity.

223

CNS Drug ReviewsVol. 11, No. 2, pp. 223–226© 2005 Neva Press, Branford, Connecticut

Address correspondence and reprint requests to: Alexander Scriabine, M.D., Department of Pharmacology,

Yale University School of Medicine, New Haven, CT 06520, USA.

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DP1287

J. D. S. Holt et al. (Enhance Biotech et al., Durham, NC, USA) described a non-

peptide ä receptor agonist, DPI-289 (chemical structure has not been released), with oral

antidepressant-like activity. DPI-289 binds selectively to ä receptors with Ki of 0.7 nM. In

rat forced swim test (FST) DPI-289 decreased immobility count at 1 mg�kg p.o. and

higher doses. The effect was dose-dependent. The effect on immobility was associated

with the increased swimming and climbing activities. These effects were completely

blocked by naltrindole, 30 mg�kg s.c. At doses up to 40 mg�kg p.o. DPI-289 had no con-

vulsant activity. At 10 mg�kg p.o. DPI-289 was still effective after 7 or 14 daily doses.

DPI-289 appears to be superior to either fluoxetine or bupropion, which had no significant

activity in FST by subchronic oral administration.

H. N. Zhang et al. (Univ. of Michigan and Mental Health Research Institute, Ann

Arbor, MI, USA) studied behavioral effects of endogenous opioid peptides (EOP) and

their effects on the expression of brain-derived neurotrophic factor (BDNF) mRNA in rats.

Met-enkephalin and leu-enkephalin, at 100 nmol i.c.v., decreased immobility of rats in the

forced swim test (FST) and increased BDNF mRNA expression in the hippocampus of

rats. Naltridole blocked the effects of enkephalins. This study is the first demonstration

that enkephalins have antidepressant activity similar to that of synthetic ä opiod agonists.

H. Zhang et al. (Univ. of Tennessee, Memphis, TN, USA) studied interaction of â-ad-

renoceptor agonists and rolipram in rats subjected to the 72-sec DRL schedule. â1-Agonist

dobutamine and â2–agonist, clenbuterol produced antidepressant-like effects; they af-

fected reinforcement rate and decreased response rate. Rolipram, a PDE4 inhibitor, at

doses below those having behavioral effects, potentiated antidepressant-like effects of

â-agonists. Combinations of ineffective doses of rolipram and clenbuterol or dobutamine

were also effective. cAMP accumulation was increased in rat cerebrocortical neurons

(primary cultures) by combination of subeffective concentrations of rolipram and

clenbuterol, but not by a combination of subeffective concentrations of rolipram and

dobutamine.

Antipsychotics

J. Lameh et al. (Acadia Pharmaceuticals, San Diego, CA, USA) studied pharmacology

of clozapine derivatives in an attempt to find a clozapine analog with lesser side effects to

treat positive and negative symptoms of schizophrenia. They identified N-desmethylclo-

zapine, a metabolite of clozapine as an effective muscarinic M1 receptor agonist and as a

potential antipsychotic candidate. They proposed that M1 receptor activation plays an im-

portant role in the mechanism of antipsychotic action of clozapine.

Cognition Activators

J. J. Buccafusco et al. (Med. College of Georgia, Augusta, GA, USA) studied the ef-

fects of cotinine on the delayed matching accuracy and attention using Delayed-Match-

ing-to Sample task (DMTS) in aged monkeys. At 0.1 to 10 mg�kg cotinine improved

accuracy in Medium and Long delay trials and reversed distractor-impaired task perfor-

mance. The study was vehicle controlled. The effect was significant even at the 0.1 mg�kg

CNS Drug Reviews, Vol. 11, No. 2, 2005

224 A. SCRIABINE

level. Cotinine does not induce nicotine-like craving and has potential as a cognition

activator.

M. S. Wolfe (Harvard Univ., Boston, MA, USA) lectured on ã-secretase inhibition as

the therapeutic objective in the treatment of Alzheimer’s disease and mentioned that short

helical peptides inhibit ã-secretase and that his group identified a peptide that inhibits the

enzyme with an IC50 = 140 pM.

Analgesics

B. D. Fisher and L. A. Dykstra (Univ. of North Carolina at Chapel Hill, NC, USA)

found that NMDA receptor antagonist, LY235959 [(–)-6-phosphonomethyl-deca-hydro-

isoquinoline-3-carboxylic acid] potentiates the antinociceptive effects of opioids using

hotplate and tail-flick procedures in mice. At 0.32 to 1 mg�kg i.p. LY235959 enhanced the

antinociceptive effects of buprenorphine, morphine, or etorphine by 40 to 300%. The

degree of enhancement was dependent on the dose of LY235959 and antinociceptive

measure, but not on the efficacy of the opioids at the ì-receptors.

J. O’Neill et al. (Ardent Pharmaceuticals, Durham, NC, and GlaxoSmithKline, Re-

search Triangle Park, NC, USA) found that the therapeutic index of the mixed opioid ag-

onist and potent analgesic, DPI-3290 [(+)3-((a-R)-a((2S,SR)-4 allyl 2,5-dimethyl-1-pipe-

razinyl-3-hydroxybenzyl)-N-(3-fluorophenyl)-N-methylbenzamide], is superior to that of

ì–receptor selective analgesics in rats. DPI-3290 produced limited tolerance to ì-anal-

gesics and less propensity for reward. It is expected to have less addiction potential than

currently used opioids.

Neuroprotective drugs

C. Kiewert et al. (Texas Tech School of Pharmacy, Amarillo, TX, USA) described

neuroprotective effects of NGP1-01, a polycyclic amine. NGP1-01 was previously

reported to block L-type voltage operated calcium channels in cardiomyocytes and to

reduce NMDA-induced calcium influx into neuronal synaptosomes. In the current study

GP1-01 at 1 to 10 ìM inhibited KCl- as well as NMDA-induced calcium influx in neuro-

nal cell cultures. In vivo, in a microdialysis study NGP1-01 at 10 to 40 mg�kg i.p. reduced

NMDA-induced membrane breakdown in rats. Since GP1-01 is capable of blocking both

major neuronal calcium channels, it can be considered a promising lead for a neuroprotec-

tive drug.

A. G. Kanthasamy et al. (Iowa State Univ., Ames, IA, USA) discovered a peptide in-

hibitor (z-DIPD-fmk), which antagonizes MPP+- or 6-OHDA-induced caspase-3 activa-

tion and DNA fragmentation in dopaminergic neurons in vitro. It prevents oxidative

neuronal apoptosis.

CNS Drug Reviews, Vol. 11, No. 2, 2005

MEETING REPORT 225

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Cotinine

D. Smith III et al. (Univ. of Pittsburgh, Pittsburgh, PA, USA) found that glial cell line

derived neurotrophic factor (GDNF) protects dopamine neurons from 6-OHDA-induced

oxidative stress. The mechanism of neuroprotective action of GDNF appears to involve

activation of MAP kinases.

According to J. Shaikh et al. (Univ. of Mississipi, MS, USA) methamphetamine (M) is

neurotoxic to monoamine neurons in mouse striatum. In vivo M, at 5 or 10 mg�kg, causes

hyperthermia and decreases striatal dopamine levels. The mechanism of M neurotoxicity

appears to involve sigma receptors. ó1 and ó2 receptor antagonists (AC297 and BD1063)

antagonized M neurotoxicity. Both antagonists together provide better protection than

either antagonist alone.

M. P. Nambiar et al. (WRAIR, Silver Springs, MD, USA) found that the adenosine1

receptor agonist (PD 81, 723; 2-amino-4,5-dimethyl-3-thienyl-[3-(trifluoromethyl) phe-

nyl] methanone) protects rats from convulsions induced by organophosphate, DFPP, and

the chemical warfare nerve agent, CWNA. The mechanism appears to involve reduction

of acetylcholine formation.

CNS Drug Reviews, Vol. 11, No. 2, 2005

226 A. SCRIABINE

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BD 1063