SYNTHESIS OF ACHATIN-I (GLY-D-PHE-L-ALA-L-ASP) ANALOGS HAVING DEHYDROPHENYLALANINE OR AMINOISOBUTYRIC-ACID RESIDUE AT POSITION-2, AND THEIREFFECTS ON ACHATINA GIANT-NEURONS

1. Achatin-I (Gly-D-Phe-L-Ala-L-Asp), a neuroactive tetrapeptide havin g a D-phenylalanine residue, has been proposed to be an excitatory neu rotransmitter of Achatina giant neurons. It was revealed that the D-Ph e(2) residue is essential for bioactivity of achatin-I, which seems to adopt beta-turn conformation. In the present study, in order to inves tigate the structure-activity relationships of achatin-I and its deriv atives, the two highly constrained analogs of achatin-I, [Delta(z)Phe( 2)]achatin-I (Gly-Delta(z)Phe-L-Ala-L-Asp) (Delta(z)Phe: (Z)-alpha,bet a-dehydrophenylaranine) and [Aib(2)]achatin-I (Gly-Aib-L-Ala-L-Asp) (A ib: alpha-aminoisobutyric acid), were synthesized, and their effects o n the two identifiable Acha tina giant neuron types, PON (periodically oscillating neuron) and v-RCDN (ventral-right cerebral distinct neuro n), were examined in comparison with those of achatin-I under voltage clamp. 2. Achatin-I (n=6), ejected onto the neurone by brief pneumatic pressure (2 kg/cm(2), 400 ms, 10(-3) M, at 10-min intervals), produce d an inward current (I-in) on PON. The I-in value (mean+/-SEM) was 0.4 4+/-0.03 nA. The interval between the achatin-I ejection and the I-in peak was 14.74+/-3.15 s (n=6). [Delta(z)Phe(2)]achatin I (n=6) and [Ai b(2)]achatin-I (n=6) had no effect on this neuron type. 3. On the othe r hand, achatin-I (n=10) and [Delta(Z)Phe(2)]-achatin-I (n=10), ejecte d by brief pressure, produced an I-in on v-RCDN. The I-in values were 0.851+/-0.07 nA for achatin-I and 0.48+/-0.05 nA (p<0.01, compared wit h that of achatin-I by Student's t-test for paired data) for [Delta(z) Phe(2)]achatin-I. The intervals between the compound ejection and the I-in peak were 5.95+/-0.33 s for achatin-I and 8.70+/-0.81 s (p<0.05, compared with that of achatin-I) for [Delta(z)Phe(2)]achatin-I. [Aib(2 )]achatin-I (n=10) had no effect on this neuron type. Copyright (C) 19 97 Elsevier Science Inc.