Table 1.

Non-classical α-conotoxins and their pharmacology.

Superfamily	Sequence, Cysteine Framework and Connectivity	Pharmacology
A superfamily
AuIB		non-competitive inhibitor of the α3β4 [99]
AuIB		10-fold more potent in rat parasympathetic ganglions than the globular isomer
AusIA		Defines a new 5/5 subclass. Both globular and ribbon isomers are equipotent at α7 [101]
ImII		Lacks conserved proline in loop 1. Allosteric inhibitor of the α7
LtIA		Ala-Xaa-Ala motif substitutes the conserved Ser-Xaa-Ser motif. Competitive blocker with a shallow binding pocket.
Lp1.1		Ala-Xaa-Ala motif substitutes the conserved Ser-Xaa-Ser motif
MrIC		State dependent activator of the α7
Eu1.6		α-conotoxin inhibiting Cav 2.2 [107]
S superfamily
RVIIIA	KCNFDKCKGTGVYNCG(Gla)SCSC(Gla)GLHSCRCTYNIGSMKSGCACICTYY	Atypical cysteine framework. Cysteine connectivity unknown. No C-terminal amidation. Two γ-carboxyglutamates. Broad selectivity: α7, α6/α3β2β3, α3β2 and to a smaller extent the α3β4 and α4β2 [9]
GVIIIA	GCTRTCGGOKCTGTCTCTNSSKCGCRYNVHPSG(BTr)GCGCACS *	Cysteine connectivity unknown. C-terminal amidation and bromo-tyrosine present as post-translational modification. Selective α9α10 inhibitor
D superfamily
VxXXA	DVQDCQVSTOGSKWGRCCLNRVCGPMCCPASHCYCVYHRGRGHGCSC	Dimeric peptides. Allosteric inhibitors of the α7, α3β2 and α4β2.
VxXXB	DD(Gla)S(Gla)CIINTRDSPWGRCCRTRMCGSMCCPRNGCTCVYHWRRGHGCSCPG
VxXXC	DLRQCTRNAPGSTWGRCCLNPMCGNFCCPRSGCTCAYNWRRGIYCSC
GeXXA		Dimeric peptide. Allosteric inhibitors of the α9α10. ‘Lid covering’ binding mode.
B3 superfamily
VxXXIVA		Potency dependent on disulfide connectivity—[1,2] 1.2 µM > [1,3] 3.9 µM > [1,4] > 30 µM, suggesting that the novel cysteine framework is important for its mode of action [26]
O1 superfamily
GeXIVA		Inhibits α9α10 nAChR subtype with no activity at the Cav channels [29]. only four cysteine residues as opposed to 6 Potency: bead isomer > ribbon isomer > globular isomer Highly charged molecule. Allosteric mode of action.
T superfamily
TxVC		α4β2 inhibitor. Members of this superfamily typically target Cav channels.
J superfamily
pl14a		Targets Kv1.6 and α3β4
M superfamily
CnIIIC		Targets Nav 1.2, 1.4 together with α3β2

(*) C-terminal amidation, (Gla) Gamma carboxylic glutamic acid, (BTr) bromotyrosine, (†) forms inter-chain disulfide bonds (Z) Pyroglutamic acid.